TW200948788A - 5-hydroxypyrimidine-4-carboxamide compounds - Google Patents

Abstract

The present invention provides the compound for promoting the production of the erythropoietin. A compound is shown by following general formula (1), [wherein, R1 represents a group of-X-Q1, -X-Q1-Y-Q2 or -X-Q1-Y-Q2-Z-Q3, X represents a single bond, -CH2-, and etc., Q1 represents a monocyclic or a bicyclic hydrocarbon group, which may be substituted with one or two substituent groups selected from substituents α , wherein the substituents α represents a group consisting of a halogen atom, an oxo group, and etc., Y represents a single bond, -CH2-, and etc., Q2 represents a monocyclic or a bicyclic hydrocarbon group, or a monocyclic or a bicyclic hetrocycloic-ring group, which may be substituted with one or two substituent groups selected from substituents β , wherein the substituents β represents a group consisting of a halogen atom, an oxo group, and etc., Z represents a single bond, -CH2-, and etc., Q3 represents a phenyl group, which may be substituted with one or two substituent groups selected from substituents γ , a C3 to C7 cycloalkyl group, which may be substituted with one or two substituent groups selected from substituents γ , a C3 to C7 cycloalkenyl group, which may be substituted with one or two substituent groups selected from substituents γ , or a monocyclic or a bicyclic hetrocycloic-ring group, which may be substituted with one or two substituent groups selected from substituents γ , wherein the substituents γ represents a group consisting of a halogen atom, an oxo group, and etc., R2 represents a C1 to C3 alkyl group, methylsulfanyl group, and etc., R3 represents a hydrogen atom, and etc., ], or the pharmaceutically acceptable salt thereof.

Description

200948788 VI. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a low molecular compound for inducing the production of erythropoietin (previously known). Erythropoietin (hereinafter referred to as EP0) is erythrocyte hematopoiesis. The lack of glycoprotein hormones, usually secreted by the kidneys, acts on the red blood cell stem cells of the bone marrow to promote red blood cell production. In the case of a low-grade disease (such as chronic kidney failure) accompanied by endogenous EP0, anemia is caused by a decrease in red blood cell production, and a supplementary therapy based on recombinant human EP0 is performed. However, genetically recombinant human EP0 is a biological preparation and has a high medical cost, and is not convenient for injection, and has an indication of shortcomings such as antigenicity. On the one hand, a low molecular weight EP0 inducer is known as a pyridine derivative, a porphyrin derivative, a porphyrin derivative, and an iso-salvin derivative (refer to Patent Documents 1 to 6, 8), 6-hydroxy-2,4 dioxometer. A compound such as a quinone-tetrahydropyrimidine derivative (see Patent Document 7). [PRIOR ART DOCUMENT] [Patent Document 1] International Publication No. 2003/049686 Booklet [Patent Document 2] International Publication No. 2003/053997 Booklet [Patent Document 3] International Publication No. 2004/108681 [Patent Document 4] International Publication No. 2006/13 3391 Booklet [Patent Document 5] International Publication No. 2007/03857 No. 1 Booklet 200948788 [Patent Document 6] International Publication No. 2007/1 36990 Booklet [Patent Document 7] International Publication No. 2007/1 5001 No. 1 Booklet [Patent Document 8] International Publication No. 2008/002576 Booklet [Summary of the Invention] The present inventors have provided excellent EPO production capacity, The low molecular novel compounds useful for the treatment of diseases caused by the low EPO are further studied for the purpose of providing these medicines. (Means for Solving the Problem) In order to solve the above problems, the present inventors have found that a novel compound having a 5-hydroxypyrimidine-4-carboxamide structure has excellent EPO productivity and is low in erythropoietin. The treatment of the cause of the disease is effective, and the present invention has finally been completed. The present invention provides a novel 5-hydroxypyrimidine-4-carboxyguanamine compound of the following formula (1) or a pharmacologically acceptable salt thereof (hereinafter referred to as a compound of the present invention). Q, that is, the invention is [1] a compound of the following formula (1) or a pharmacologically acceptable salt thereof,

[In the formula (1), R1 is a group represented by -X-Q1, -X-Q'-Y-Q2, or -X-Q'-YQ^Z-Q3, and X is a single bond, -CH2-, -(CH2)2·, -(CH2)3-, -ch2〇-, -och2-, 200948788 Ο-, -S-, or -CO-, Q1 is one which may be selected by the substituent group α or a monocyclic or bicyclic hydrocarbon ring group of two substituents (the hydrocarbon ring group includes an aromatic tonic ring and a non-aromatic hydrocarbon ring of 3 to 1 member), and the substituent group α is a halogen atom and a pendantoxy group. , hydroxy, Ci~C6 yard base, halogenated Ci~C6 yard base, Ci~C6 institute oxy-halogenated Ci~c6 alkoxy group, and c2~C7 alkyl fluorenyl group, Y is a single bond, -CH2 -, -(CH2)2-, -(CH2)3-, -CH20_, _OCH2-, _(CH2)2-, -0-, -S-, -NH-, -NCHj-, or -C0- , 〇Q2 is a monocyclic or bicyclic hydrocarbon ring group which may have one or two substituents which are not selected by the substituent group (the hydrocarbon ring group includes an aromatic smoke ring and a non-aromatic group of 3 to 1 member) a hydrocarbon ring), or a monocyclic or bicyclic heterocyclic group which may have one or two substituents selected from the substituent group /3 (the heterocyclic group includes 4 to 1 member aromatic heterocyclic ring) Non-aromatic heterocyclic ring containing nitrogen atom, sulfur One or two atoms selected from the group consisting of oxygen and oxygen atoms, and the substituent group β is a halogen atom, a pendant oxy group, a hydroxyl group, an amine group, a cyano group, a n Cl~Ce or a halogenated Cl~C6 yard base. , Cl~C6 oxy, g-Cl~C6 alkoxy, ◦~c6 alkylamino, (〇~c6 alkyl) ((:,~c6) amino group, and C2~C7 alkane a group of radicals, Z is a single bond, -CH2-, -(CH〇2:, -OCH2-, -0-, -S-, -NH-, _N(CH〇-, or -CO-, Q3 is a phenyl group which may have one or two substituents selected from the substituent group 7, and may have one or two substituents selected from the substituent group r, c3 to c7 200948788 cycloalkyl group, which may be a c3~C7 cycloalkenyl group of one or two substituents selected by the substituent group r, or a monocyclic or bicyclic heterocyclic group which may have one or two substituents selected from the substituent group r ( The heterocyclic group includes 4 to 10 membered aromatic heterocyclic rings and non-aromatic heterocyclic rings, and 1 or 2 of the atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, and the substituent group r is a halogen atom. , side oxy, hydroxy, amine, cyano, C!~C6 alkyl, halogenated alkyl, 〇~(: 6 alkoxy, halogenated (^~ Ce hospitaloxy, Cl~Ce-based amine, (Cl~C6) (Ci~Ce) amine, and C2~C7 alkyl fluorenyl, R2 is alkane a group, a cyclopropyl group, a methyl sulfanyl group, a fluoromethyl group, or a difluoromethyl group, R3 is a hydrogen atom or a methyl group. [2] X is a single bond, -CH2-, or -(CH2)2- The compound of the above [1] or a pharmacologically acceptable salt thereof. [3] The compound of the above [1] wherein X is a single bond or the pharmacologically acceptable salt thereof [4] Q1 is a cyclopentyl group or a cyclohexyl group which may have one or two substituents selected from the substituent group α. Cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, naphthyl, tetrahydronaphthyl, decahydronaphthyl, hydroquinone, nonenyl, or fluorenyl The compound according to any one of the items 1 to 3, or a pharmacologically acceptable salt thereof. [5] Q1 is any of the above-mentioned [1] to [3] of the above-mentioned [1] to [3] which may have one or two substituents selected from the substituent group α, such as cyclohexyl, cyclohexenyl, phenyl or naphthyl. A compound or a pharmacologically acceptable salt thereof. [6] Q1 is a compound of any one of the above [1] to [3] which may have a cyclohexyl group, a cyclohexenyl group or a phenyl group which may have one or two substituents selected from the substituent group α or Its pharmacological salt is allowed. [7] The substituent group α is the above-mentioned groups [1] to [6] in which the group of the dentate atom, the thiol group, the Ci~-house group, the halogenated Ci~C6 alkyl group, and the C!~(:6 alkoxy group) A compound according to any one of the above, or a pharmacologically acceptable salt thereof. [8] The substituent group α is a group of a fluorine atom, a chlorine atom, a hydroxyl group, a tert-butyl group, a difluoromethyl group, and a hexyloxy group. (1) to [6], wherein the compound or a pharmacologically acceptable salt thereof is a compound of the formula (9), wherein R1 is -X-Q'-YQ or -X-qi.Y_q, z_q3, and Y is A compound of any one of the above [1] to [8], which is a single bond, -CH2-, -(CH2)2-, -0(CHz)2-, -〇-, -NH-, or -NCH3- Or a pharmacologically acceptable salt thereof. [10] Y is a single bond, -〇_, -CH2-, or -NH_, the compound of the above [9] or a pharmacologically acceptable salt thereof. q [11] R1 is -X-Q a group represented by '-Y-Q2, or -X-Q'-Y-Q'Z-Q3, and Q2 is a cyclopentyl group or a cyclohexyl group which may have one or two substituents selected from the substituent group yS , cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, naphthyl, tetrahydronaphthyl, decahydronaphthyl, hydroquinone, decenyl, Sulfhydryl, tetrahydrofuranyl, tetrahydropyranyl, didecylalkyl, dioxanyl, dioxaheptyl-aziridine, pyrrolidinyl, piperidinyl, azepine, piperazine , dihydrocarbazolyl, dihydrothiazolyl, morpholinyl, pyrrolyl, 200948788

Dihydropyrrolyl, pyridyl, dihydropyridyl, tetrahydropyridyl, thienyl, furyl, pyrimidinyl, hydrazine, pyridinyl, pyrazolyl, thiazolyl, isothiazolyl, carbazolyl, Isoxazolyl, chromoalkyl, isochroman, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothiophenyl, fluorenyl, isodecyl, quinolinyl, Tetrahydrogalinyl, isoquinolyl, tetrahydroisophyllinyl, benzoxazolyl, quinoxalinyl, benzothiazolyl, benzodioxanyl, fluorenyl, thienopyridinyl, A compound according to any one of the above [1] to [1], or a pharmacologically acceptable salt thereof, which is a dihydrothienopyridinyl group, a furopyridylpyridyl group or a dihydrofuropyridinyl group. [12] Q2 is a cyclohexyl group, a cyclohexyl group, a phenyl group, a piperazine group, a fluorene group, or a chelate group which may have one or two substituents which are not selected by the substituent group. The compound described or its pharmacologically acceptable salt. [13] The compound of the above [11] or a pharmacologically acceptable salt thereof, which is a phenyl group, a piperidinyl group, a pyridyl group or a pyrimidinyl group which may have one or two substituents selected from the substituent group /3. [14] R1 is a group represented by -X-Q'-Y-Q2 or -X-Q'-YQ^Z-Q3, and the substituent group β is a halogen atom, a hydroxyl group, a cyano group, a 〇~C6 alkyl group. , g (^6 (6 alkyl, cesium halide ~ (6 alkyl, C, ~ C6 alkoxy, cesium halide ~ (6 alkoxy, ο ~ C7 alkyl fluorenyl group) The compound according to any one of the above [1] to [13] or a pharmacologically acceptable salt thereof. [15] The substituent group β is a fluorine atom, a chlorine atom, a hydroxyl group, a cyano group, a methyl group, a tert-butyl group, and a The compound of the above [14] or the pharmacologically acceptable salt thereof, which is a group of an oxy group, a trifluoromethyl group, a trifluoromethoxy group, and an ethylenic group, 200948788 [16] R1 is -X-Q'-Y-Q a compound of any one of the above [1] to [15], wherein Z is a single bond, -CH2-, -OCH2-, -Ο-, -NH-, or -CO- Or a pharmacologically acceptable salt thereof. [17] The compound of the above [16] wherein Z is a single bond, -CH2-, -0-, or -C0- or a pharmacologically acceptable salt thereof. [18] R1 is -X-Ql- a group represented by Y-Q2-Z-Q3, and Q3 is a cyclopropyl group, a cyclobutyl group or a cyclopentyl group which may have one or two substituents selected from the substituent group r , cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, didecylalkyl, dioxanyl, dioxane Cycloalkyl, aziridinyl, pyrrolidinyl, piperidinyl, azepine, dihydrocarbazolyl, dihydrothiazolyl, morpholinyl, pyrrolyl, dihydropyrrolyl, pyridyl, dihydropyridine Base, tetrahydropyridyl, thienyl, furyl, pyrimidinyl, fluorenyl, pyridyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, chromoalkyl, isochroman Benzo, benzofuranyl, dihydrobenzopyranyl, benzothienyl, dihydrobenzene q-thienyl, fluorenyl, isodecyl, quinolinyl, tetrahydroquinolyl, isoquino Lolinyl, tetrahydroisoquinolyl, imidazopyridyl, benzoxazolinyl, quinoxalinyl, benzothiazolyl, benzodioxanyl, oxime, thienopyridyl, dihydrogen The compound of the above [1] to [17] or a pharmacologically acceptable salt thereof, [19] Q3 is a thienopyridyl group, a furopyridyl group, or a dihydrofuropyridinyl group. There may be a compound of the above [18] or a pharmacologically acceptable salt thereof, which is one or two substituents selected from the substituent group 7 and a base group or a terminal group of the substituents, and [20] Q3 may be substituted The compound of the above [18] or the pharmacologically acceptable salt thereof, wherein the radical group r is selected from one or two substituents, and [21] R1 is represented by -X-Qi-Y-Q'Z-Q3 The compound or a pharmacologically acceptable salt thereof according to any one of the above [1] to [20], wherein the substituent group r is a group of the fluorine atom and the hydroxyl group.

[22] The compound according to any one of the above [1] to [21] wherein R2 is a methyl group, an ethyl group, a methylthioalkyl group, a fluoromethyl group or a difluoromethyl group, or a pharmacologically acceptable salt thereof. [23] The compound according to any one of the above [1] to [21], or a pharmacologically acceptable salt thereof, wherein R2 is a methyl group or a methylthiophene group. [24] A compound according to any one of the above [1] to [21], wherein R3 is a hydrogen atom, or a pharmacologically acceptable salt thereof. Further, it is as follows: [25] In the above [1], R1 is a group represented by -X-Qi-Y-Q2, and X is a single bond, -CH2-, or -(CH2)2-, and Q1 may be substituted The group α is selected from one or two substituents of a phenyl 'cyclohexenyl group or a cyclohexyl group, and the substituent group α is a group consisting of a fluorine atom and a chlorine atom, and Υ is a single bond, -CH2-, - 0-, or -ΝΗ-, Q2 is a cyclohexyl group, a cyclohexenyl group, a phenyl group, a piperidinyl group, a pyridyl group or a pyrimidyl group which may have one or two substituents selected from the substituent group ,. -11- 200948788 The substituent group a is a compound of a group consisting of a fluorine atom, a chlorine atom, a methyl group, a tert-butyl group, and a trifluoromethyl group, or a pharmacologically acceptable salt thereof. [26] In the above [25], Q2 is a compound which may have one or two substituents selected from the substituent group /S, a phenyl group, a steep group, a fluorenyl group, or a succinic group or a pharmacologically acceptable compound thereof. salt. [27] In the above [1], R1 is a group represented by -X-Q'YQ^Z-Q3, X is a single bond, and Q1 is one or two substituents which may be selected from the substituent group Q: a phenyl group, a cyclohexenyl group or a cyclohexyl group, wherein the substituent group α is a group consisting of a hydroxyl group, a hydrazine is a single bond, -〇-, or -ΝΗ-, and Q2 is a phenyl group, a piperidinyl group, or a pyridyl group. , Ζ is a single bond, -CH2-, -〇-, -ΝΗ-, or -CO-, Q3 is a phenyl or pyridyl group which may have one or two substituents selected from the substituent group r, a substituent The group T is a compound of a group consisting of a fluorine atom and a hydroxyl group or a pharmacologically acceptable salt thereof. [28] In the above [27], Q2 is a phenyl group or a pyridyl group which may have one or two substituents which are not selected from the substituent group, and Q3 may be one or two which may be selected from the substituent group r. a phenyl or pyridyl compound of a substituent or a pharmacologically acceptable salt thereof. 200948788 [29] In the above [1], a compound selected by the following or a pharmacologically acceptable salt thereof; ({[2-(biphenyl-4-ylmethyl)-5-hydroxy-6-methylpyrimidin-4- Alkyl]carbonyl}amino)acetic acid, [({2-[(4'-fluorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino] Acetic acid, ({[2-(4-cyclohex-1-en-1-ylbenzyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid, { [(5- Hydroxy-6-methyl-2-{[4'-(trifluoromethyl)biphenyl-4-yl]methyl}pyrimidin-4-yl)carbonyl]amino}acetic acid, ({[5-hydroxy- 6-Methyl-2-(1,1':4',1"-bitriphenyl-4-ylmethyl)pyrimidin-4-yl]carbonyl}amino)acetic acid, [({5-hydroxy-) 6-Methyl-2-[(4-phenylcyclohex-1-en-1-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid, [({2-[(4' - Tert-butylbiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid, [({2-[4-(5-benzylpyridine) -2-yl)benzyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid, {[(5-hydroxy-6-methyl-2-{[4'-( Pyridin-3-ylmethyl)biphenyl-4-yl]methyl}pyrimidin-4-yl)carbonyl]amino} Acid, {[(5-hydroxy-6-methyl-2-{[4,-(pyridin-4-ylmethyl)biphenyl-4-yl]methyl}pyrimidin-4-yl)carbonyl]amino) }Acetic acid, {[(5-hydroxy-6-methyl-2-{[4'-(pyridin-2-ylmethyl)biphenyl-4-yl]methyl} -13- 200948788 pyrimidin-4-yl Carbonyl]aminopurine acetic acid, [({5-hydroxy-6-methyl-2-[4-(4-phenylpiperidin-;l-yl)benzyl]pyrimidin-4-yl}carbonyl)amine Acetic acid, {[(2-{[trans-4-(4'-fluorobiphenyl-4-yl)cyclohexyl]methyl) 5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amine Based on acetic acid, {[(2-{[trans-4-(4-benzylphenyl)cyclohexyl]methyl) 5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid, {[(5-Hydroxy-6-methyl-2-{[trans-4-(4-pyridin-2-ylphenyl)cyclohexyl]methyl}pyrimidin-4-yl)carbonyl]amino}acetic acid, Ο {[(5-Hydroxy-6-methyl-2-{[trans-4-(4-pyridin-3-ylphenyl)cyclohexyl]methyl}-pyrimidin-4-yl)carbonyl]aminopurine Acetic acid, {[(5-hydroxy-6-methyl-2-{[4-(4-phenoxyphenyl)cyclohex-3-en-1-yl]methyl}pyrimidin-4-yl)carbonyl] Amino)acetic acid, {[(5-hydroxy-6-methyl-2-{[4-(4-phenoxyphenyl)cyclohexyl]methyl}pyrimidin-4-yl)carbonyl) Amino}acetic acid, ([U-{[trans-4-(biphenyl-4-yloxy)cyclohexyl]methyl b 5-hydroxy-6-methylpyrimidinium-4-yl)carbonyl] Amino}acetic acid, and U(2-{[trans-4-(biphenyl-4-ylamino)cyclohexyl]methyl}-5-hydroxy-6.methylpyran-4-yl)carbonyl] Amino indenoacetic acid. [30] A pharmaceutical composition comprising the compound according to any one of the above [1] to [29] or a pharmacologically acceptable salt thereof as an active ingredient. [31] The medicine according to the above [30] for use in the prevention and/or treatment of anemia. 14-200948788 [32] The medicine described in the above [31], wherein the anemia is renal anemia, anemia of an unripe child, accompanied by chronic diseases. Anemia, anemia associated with cancer chemotherapy, or cancerous anemia. [33] The pharmaceutical according to the above [30], wherein the erythropoietin (34) is used in the manufacture of a pharmaceutical or a pharmacologically acceptable salt thereof according to any one of the above [1] to [29]. .

[35] The use according to the above [34], wherein the medicine is a medicine for preventing and/or treating anemia. [36] The use according to the above [34], wherein the anemia is renal anemia, anemia of an unripe child, anemia accompanied by chronic diseases, anemia accompanied by cancer chemotherapy, or cancerous anemia. [37] A method for producing erythropoietin, which comprises administering an effective amount of the compound according to any one of the above [1] to [29] or a pharmacologically acceptable salt thereof to a mammal or a bird. [38] The method according to the above [37], which is for preventing and/or treating anemia. [39] The method according to the above [37], wherein the anemia is renal anemia, anemia of an unripe child, anemia accompanied by chronic diseases, anemia accompanied by cancer chemotherapy, or cancerous anemia. [40] The method according to the above [37], wherein the mammal is a human, a horse, a cow or a pig, and the bird is a chicken. The compound of the present invention represented by the above formula (1) is an amine skeleton having 5-hydroxypyrimidine-4-carboxyindole • 15-200948788. The point at which the substituent at the 2-position of the hydroxypyrimidine ring is substituted by a hydrocarbon ring which may be substituted by a methylene chain or the like is a chemical structural feature. The point of promoting the production of EPO is a pharmacological characteristic. Hereinafter, the substituent of the compound (1) of the present invention will be described. In the definition of the substituent group α, the substituent group 0, and the substituent group 7, the "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. In the definition of R2, "(^~匕alkyl) may be a group having 1 to 3 carbon atoms or a branched chain. For example, methyl group, ethyl group, propyl group, isopropyl group. Substituent group α, The "Ci-C6 alkyl group" in the definition of the substituent group θ and the substituent group r may be an alkyl group having 1 to 6 linear or branched chains, for example, methyl group, ethyl 'propyl group, and isopropyl group. Base, butyl, t-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, oxime-ethyl, hexyl, 4-methylpentyl, 3 -methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1,dimethylbutyl, 1'2-dimethylbutyl, 13-dimethylbutyl, 2,3 dimethylbutyl, 2 ethylbutyl, etc. Substituent group α, substituent group 0, and substituent group ^ In the definition, "toothing (^~匕院基" is a group in which one or two or more hydrogen atoms of the above "Cl~Ce alkyl group" are substituted by the above "halogen atom". For example, fluoromethyl group, chlorine group Base, bromomethyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2, 2, 2_3 Ethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl, 2,2-dibromoethyl, etc. 200948788 In the definition of the substituent group α, the substituent group /3, and the substituent group r, "C, C<i hospital oxygen" is the above "匕~ a C6 alkyl group bonded to an oxygen atom, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy, third butoxy Base, n-pentyloxy, isopentyloxy, 2-methylbutoxy, neopentyloxy, n-hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy Base, 3 3 dimethylbutoxy group,

2,2-Dimethylbutoxy, M-dimethylbutoxy, 1,2-dimethylbutoxy, 1'3-dimethylbutoxy, 2,3-dimethylbutyl Oxyl and the like. In the definitions of the substituent group α, the substituent group 々, and the substituent group r, "deuterated Cl~C6 alkoxy group" is one or more hydrogens of the above "(^~(:6 alkoxy group)" a group in which an atom is substituted by the above "halogen atom", for example, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy Base, 2,2,2-trichloroethoxy, 2,2,2-trifluoroethoxy, 2-bromoethoxy, 2-chloroethoxy, 2-fluoroethoxy, 2,2 · a group such as a dibromoethoxy group. The substituent group Θ, and the definition of the substituent group r, "c, -c6 alkylsulfanyl group" are the above-mentioned "〇^~(:6 alkyl group) bonded to a sulfur atom For example, methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, isobutylsulfanyl, dibutylsulfanyl, Tributylsulfanyl, pentylsulfanyl, isopentylsulfanyl, 2-methylbutylsulfanyl, neopentylsulfanyl, 1-ethylpropylsulfanyl, hexylsulfane Base, 4-methylpentylsulfanyl, 3-methylpentylsulfanyl, 2-methylpentylsulfanyl, 1-methylpentylsulfide , 3,3-dimethylbutylsulfanyl, 2,2-dimethylbutyl-17- 200948788 sulfanyl, 1,1-dimethylbutylsulfanyl, 1,2-di Methylbutylsulfanyl, 1,3-dimethylbutylsulfanyl, 2,3-dimethylbutylsulfanyl, 2-ethylbutylsulfuryl, etc. Substituent group /3 And the definition of the substituent group r is "匕~匕alkylamino group" which is a group in which the above-mentioned "Ci~C«i" group is bonded to an amine group, for example, a methylamino group, an ethylamino group, or a C group. Amino group, isopropylamino group, butylamino group, isobutylamino group, second butylamino group, tert-butylamino group, amylamino group, isoamylamino group, 2-methyl group Butylamino, neopentylamino, 1-ethylpropylamino, hexylamino, 4-methylpentylamino, 3-methylpentylamino, 2-methylpentylamino , 1-methylpentylamino, 3,3-dimethylbutylamino, 2,2-dimethylbutylamino, 1,1-dimethylbutylamino, hydrazine, 2- Dimethylbutylamino group, 1,3-dimethylbutylamino group, 2,3-dimethylbutylamino group, 2-ethylbutylamino group, etc. Substituent group 3, and substituent In the definition of group r, "(〇~〇ane) ( 基~(:6 alkyl)amino group" is the same or different of the above "c, ~c6 alkyl group" in the substituted group of the amine group. For example, dimethylamino group, methyl ethylamine Base, diethylamino, di-n-propylamino, diisopropylamino, N-(n-propyl)-N-ethylamino, di-n-butylamino, diisobutylamino , s-butylamino, di-tert-butylamino, di-n-pentylamino, diisoamylamino, di-2-methylbutylamino, di-n-pentylamino, two -ethylpropylamino, di-n-hexylamino, di-4-methylpentylamino, di-methylpentylamino, di-2-methylpentylamino, di-methyl-pentyl Amino group, di 3,3-dimethylbutylamino group, di 2,2-dimethylbutylamino group, di 1,1-dimethylbutylamino group, 200948788 two 1,2·two Methyl butylamino group, di 13-dimethylbutylamino group, di 2,3-dimethylbutylamino group, di-2-ethylbutylamino group and the like. The "C2 to C7 alkyl fluorenyl group" in the definition of the substituent group α, the substituent group Θ, and the substituent group r is a carbon number of 2 to 7 alkyl fluorenyl groups. For example, an ethyl group, a propyl group, a butyl group, an isobutyl group, a pentyl group, a pentylene group, an isopentenyl group, a hexyl group, a fluorenyl group, and the like. In the definition of Q3, 'C3 to C7 cycloalkyl group' is a carbon number of 3 to 7 cycloalkyl groups. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. In the definition of Ο 3 Q, "C3 to C7 cycloalkenyl" is a carbon number of 3 to 7 cycloalkenyl groups. For example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl. The "monocyclic or bicyclic hydrocarbon ring group" in the definition of Q1 and Q2 is a saturated or unsaturated hydrocarbon group having 3 to 1 unit monocyclic or bicyclic hydrocarbon groups. For example, a monocyclic aromatic hydrocarbon ring group such as a phenyl group; a monocyclic non-aromatic hydrocarbon ring group such as the above C3 to C7 cycloalkyl group or the above C3 to C7 cycloalkenyl group; naphthyl group, tetrahydronaphthyl group, decahydroquinone A bicyclic aromatic or non-aromatic hydrocarbon ring group such as a naphthyl group, a hydroquinone group, a nonenyl group or a norbornyl group. In the definition of Q2 and Q3, "monocyclic or bicyclic heterocyclic group" is a 4 to 10 member which is saturated or unsaturated with 1 or 2 atoms selected from a group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. Monocyclic or bicyclic heterocyclic groups. For example, tetrahydrofuranyl, tetrahydropyranyl, didecylalkyl, dialkyl, dioxaheptyl, aziridinyl, pyrrolidinyl, piperidinyl, anthracenyl, piperidyl, Monocyclic non-aromatic hetero-19-200948788 ring group; pyrrolyl, pyridyl, thienyl, furyl, pyrimidinyl, pyranyl, fluorenyl a monocyclic aromatic heterocyclic group such as pyridyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl; chromoalkyl, heterochromic alkyl, benzofuranyl, Dihydrobenzofuranyl, benzothienyl, dihydrobenzothiophenyl, indenyl, isodecyl, sialolinyl, tetrahydroquinolyl, isoquinolinyl, tetrahydroisoquinolinyl, a bicyclic heterocyclic group such as a benzoxazolinyl group, a benzodioxanyl group, a hydrazine group, a thienopyridyl group, a dihydrothienopyridyl group, a furopyridyl group or a dihydrofuropyrimidinyl group.

In the compound (1) of the present invention, R1 is a group represented by -X-Q1, -X-Q^Y-Q2, or -X-Qi-Y-Q^Z-Q3. When R1 is a group represented by -X-Qi-Y-Q2 or -XQ^YQ^Z-Q3, Q1 or Q2 may be a divalent substituent, and in the present specification, it is described in the same manner as the monovalent substituent. . For example, when R1 is a group represented by -XQ and Y-Q2, and Q1 is a group having a cycloalkyl structure, Q1 is a divalent substituent having a bond of X and Y "cycloalkylene (or cycloalkyldiyl) "), but is described by "cycloalkyl". The same applies to the case where y is a Q structure of another ring. Further, for example, when R1 is a group represented by -X-Ql-Y-Q2-Z-Q3, and Q2 is a group having a cycloalkyl structure, Q2 is a divalent substituent having a bond of Y and Z. Base (or cycloalkanediyl), but is described by "cycloalkyl". The same applies to the case where the other ring structure is used. Further, Q', Q2, and Q3 may have more substituents. The substitution position of the base-Y-Q2 or the base-Y-Q2-Z-Q3 in Q1 in the case where R1 is -X-Q^Y-Q2 or -X-Q^Y-Q^Z-Q3. -20- 200948788 When Q1 is a 5-membered ring and the position of the carbon atom bonded to X is a 丨 position, the substitution position of the base-Y-Q2 or the base-Y-Q2-Z-Q3 is preferably 3 or 4 positions. . When Q1 is a 6-membered ring and the position of the carbon atom bonded to X is 1 position, the substitution position of the base_Y-Q2 or the base-Y-Q2-Z-Q3 is preferably 4 bits. When Q1 is a 7-membered ring and the position of the carbon atom bonded to X is 1 position, the substitution position of the base-Y-Q2 or the base-Y-Q2-Z-Q3 is preferably 4 or 5, 〇 〇 When Q1 is a phenyl group, the substitution position of the group -Y-Q2 or the group -Y-Q2-Z-Q3 is preferably substituted by the following. Further, for example, when Q1 is a cyclohexyl group, for example, the substitution position of the base-Y-Q2 or the base-Y-Q2-Z-Q3 is preferably replaced by the following:

4" Ψ

In the present invention, X is preferably a single bond, -CHi-, or -(CH2)2-', and X is a single bond or -ch2-, and more preferably X is a single bond. The keys on the right side of each base are shown in combination with Q1 above. In the present invention, Q1 is preferably a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptyl group or a benzene which may have one or two substituents selected from the substituent group α. a group, a naphthyl group, a tetrahydronaphthyl group, a decahydronaphthyl group, a hydrogen sulfhydryl group, a nonenyl group or a fluorenyl group is particularly preferably a cyclohexyl group or a ring which may have one or two substituents selected from the group of substituents. The hexyl group, the phenyl group or the naphthyl group is more preferably 21-200948788 which is a cyclohexyl group, a cyclohexenyl group or a phenyl group which may have one or two substituents selected from the substituent group α. More preferably, it is a cyclohexyl group or a phenyl group which may have one or two substituents selected from the substituent group α. In the present invention, the substituent group α is preferably a halogen atom, a hydroxyl group, a fluorenyl group, a ruthenium halide group, a halogen group, a ruthenium group, and a ruthenium group. The group consisting of a chlorine atom, a hydroxyl group, a tert-butyl group, a trifluoromethyl group, and a hexyloxy group. Further, there may be no limitation in the substitution position in Q1 of one or two substituents selected by the substituent group α. In the present invention, the hydrazine is a single bond, -CH2-, -(CH2)2-, -0(CH〇2-, -v Ο-, -NH-, or -NCH3-, particularly preferably Y is a single bond, -Ο-, -CHi-, or -NH-, more preferably Y is a single bond. The bond on the left side of each group is shown to be bonded to Q1 above. In the present invention, Q2 is preferably one which may not be selected by the substituent group. And 2 substituents of cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, naphthyl, tetrahydronaphthyl, decahydronaphthyl, hydrogen Indenyl, nonenyl, norbornyl, tetrahydrofuranyl, tetrahydropyranyl, dioxane Q, dialkyl, dioxinyl, aziridine, pyrrolidinyl, piperidinyl , 吖heptyl, piperylene, dihydrocarbazolyl, dihydrothiazolyl, morpholine , pyridine, dihydropyrrolyl, pyridyl, dihydropyridyl, tetrahydropyridyl, thienyl 'furanyl, pyrimidinyl, oxime, pyridyl, pyrazolyl, thiazolyl, isothiazolyl , carbazolyl, isoxazolyl, chromoalkyl, isochroman, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothiophenyl, fluorenyl, isodecyl , quinolyl, tetrahydroquinolyl-22- 200948788, isoquinolinyl, tetrahydroisoquinolinyl, benzoxazolyl, quinoxalinyl, benzothiazolyl, benzodioxan,吲耕基, thienopyridyl, dihydrothienopyridyl, furopyridinyl, or dihydrofuropyridinyl, especially Q2 is one or two substituents which may be selected from the group of substituents a cyclohexyl group, a cyclohexyl group, a phenyl group, a fluorene group, a fluorene group, or a fluorenyl group, and more preferably a phenyl group or a phenyl group having one or two substituents selected from the substituent group yS. The pyridine group or the pyridyl group. In the present invention, the substituent group is preferably a halogen atom, a hydroxyl group, a cyano group, a Cl~c6 alkyl group, a halogenated group, a halogenated alkyl group, or a halogenated group. (6: alkoxy group, ruthenium halide ~ decyloxy group, C2~C7 alkyl fluorenyl group, particularly suitable for the group consisting of fluorine atom, chlorine atom, hydroxyl group, cyano group, methyl group, third group a group consisting of a trifluoromethyl group, a methoxy group, a trifluoromethoxy group, and an ethyl fluorenyl group, more preferably a fluorine atom, a chlorine atom, a methyl group, a tert-butyl group, or a trifluoromethyl group. In the present invention, Z is preferably a single bond, -CH2-, -OCH2-, -0. -, -NH-, or -CO-, particularly preferably a single bond, -CH2-, -◦-, -NH·, or -CO-, more preferably Z is a single bond, -CH2-, -C0-, or _〇-. The keys on the left side of each base are shown in combination with Q2 above. In the present invention, Q3 is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclopentenyl group or a cyclohexene which may have one or two substituents selected from the substituent group r. , cycloheptenyl, phenyl, tetrahydrofuranyl, tetrahydropyranyl, didecylalkyl, dialkyl, dioxaheptyl, aziridinyl-23- 200948788, pyrrolidinyl, piperidine Pyridyl, indenyl, dihydrocarbazolyl, dihydrothiazolyl, morpholinyl, pyrrolyl, dihydropyrrolyl, pyridyl, dihydropyridyl, tetrahydropyridyl, thienyl, furyl, Pyrimidinyl, fluorenyl, pyridinyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, chromoalkyl, isochroman, benzofuranyl, dihydrobenzofuranyl , benzothienyl, dihydrobenzothiophenyl, fluorenyl, isodecyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolinyl, imidazopyridyl, benzene And oxazoline group, quinoxalinyl, benzothiazolyl, benzodioxanyl, fluorenyl, thienopyridyl, dihydrothienopyridyl, furopyridinyl hydrazine Hydrofuropyridylpyridyl, particularly preferably Q3 is a phenyl or pyridyl group which may have one or two substituents selected from the substituent group γ, and more preferably Q3 may be one or two selected from the substituent group r. a pyridyl group of a substituent. In the present invention, the substituent group r is preferably a group of a fluorine atom and a hydroxyl group, and one or two substituents selected from the substituent group r may be substituted in the Q3. In the present invention, R2 is preferably a methyl group, an ethyl group, a methylthioalkyl group, a fluoromethyl group or a di-Q-methyl group, and particularly preferably R2 is a methyl group or a methylthioalkyl group. In the present invention, R3 is preferably a hydrogen atom. In the present invention, when R1 is a group represented by -X-Q'Y-Q2, a preferred combination of X, Qi, substitution 0:, Y, Q2, and a substituent group point is X is a single bond, 'CH2- Or -(ch〇2- 'Q1 is a phenyl group, a cyclohexenyl group or a cyclohexyl group which may have one or two substituents selected from the substituent group α, and the substituent group α is a fluorine atom, and a group of chlorine atoms, Υ is a single bond, -CH", -〇- -24- 200948788, or -NH-, and Q2 is a ring of one or two substituents which may be selected by the substituent group /3 The hexyl, cyclohexenyl, phenyl, piperidinyl, pyridyl, or pyridyl' substituent group is not formed by a fluorine atom, a chlorine atom, a methyl group, a tert-butyl group, or a trifluoromethyl group. In such a combination, X is preferably a single bond, and Q1 is preferably a phenyl group or a cyclohexyl group which may have one or two substituents selected from the substituent group α, and is a single bond, -〇- Or, preferably, q2 is more preferably a phenyl group, a stilbene group, a pyridyl group or a pyrimidyl group which may have one or two substituents selected from the substituent group /3. When R1 is not -XQ^YC^-Z-Q3, X, Q1, substituent group α, Y, Q2, Z, Q A preferred combination of 3 and the substituent group 7 is that X is a single bond, and Q1 is a phenyl group, a cyclohexyl group or a cyclohexyl group which may have one or two substituents selected from the substituent group α, and a substituent group α is a group formed by a hydroxyl group, Υ is a single bond, -〇-, or -ΝΗ-, Q2 is a phenyl group, a piperylene group, or a squid group, Ζ is a single bond, -CH2-, -〇-, ΝΗ-, or -CO-, Q3 is a group of a benzene Q group or a pyridyl group which may have one or two substituents selected from the substituent group r, and a substituent group j is a group of a fluorine atom and a hydroxyl group. In such a combination, it is preferred that Q1 is a phenyl group or a cyclohexyl group which may have one or two substituents selected from the substituent group α, and Υ is a single bond, -0-, or -ΝΗ- preferably, Q2 Preferably, it is a phenyl group or a pyridyl group, hydrazine is a single bond, -CH2-, or -0- is preferred, and Q3 is a pyridyl group. The compound of the present invention has a geometric isomer depending on the kind of the substituent or Where tautomers are present, and where the compounds of the invention have asymmetric carbon atoms, the present invention includes separators or mixtures of these isomers. Further -25-200948788 Targets, ie, compounds of the invention Atom above 1 A compound substituted with a radioactive isotope element or a non-radioactive isotope element is also included in the present invention. When a compound of the present invention has a basic group such as an amine group, a pharmacologically acceptable salt can be prepared as desired. Such a salt may be, for example, hydrofluoric acid. Hydrohalide salts such as acid salts, hydrochloride salts, hydrobromide salts, hydroiodide salts; inorganic acid salts of nitrates, perchlorates, sulfates, citrates, etc.; methanesulfonate, trifluoromethanesulfonate Alkane sulfonate such as acid salt or ethanesulfonate; aryl sulfonate such as benzenesulfonate or p-toluenesulfonate; acetic acid, malic acid, fumarate, succinate, citrate, cesium An organic acid salt such as tartrate, oxalate or maleate; and an amine acid salt such as alanate, ν glutamate or aspartate; preferably a hydrohalide and an organic acid salt. . Further, when the compound of the present invention has an acidic group such as a carboxyl group, a base addition salt can be generally formed. The pharmacologically acceptable salt may be an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt; an alumina metal salt such as a calcium salt or a magnesium salt; an inorganic salt such as an ammonium salt; a dibenzylamine salt, a morpholine salt, and a phenylglycolate. Alkylamine salt, ethylenediamine salt, Ν-methyl glucosamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine Q salt, hydrazine, Ν' _ dibenzyl Organic amines such as ethylenediamine salt, diethanolamine salt, bismuth-benzyl-indole-(2-phenylethoxy)amine salt, piperene salt, tetramethylsulfate salt, ginseng (hydroxymethyl) aminomethane salt Salt and so on. The compounds of the invention are also present as free bodies or solvates. The solvate is not particularly limited as long as it is pharmacologically acceptable. Specifically, a hydrate or an ethanolate is preferred. Further, in the case where a nitrogen atom is present in the compound of the formula (1), it may be a cerium-oxide, and these solvates and cerium-oxides are also included in the range of the present invention from -26 to 200948788. The compound of the present invention may have various isomers such as a geometric isomer such as a cis or a transantiomer, a tautomer, or a d or a l such as an optical isomer according to the kind or combination of the substituent, and the present invention Where the compound is not limited, these all isomers, stereoisomers, and mixtures of these isomers and stereoisomers in any ratio are also included. The compound of the present invention can be produced by a variety of known synthetic methods based on the nature of its basic skeleton or substituent. At this time, depending on the kind of the functional group, the functional group is protected by a suitable protecting group based on the stage of the raw material to the intermediate, or is replaced with a manufacturing-based technically effective effect which is easily converted into the functional group. Such functional groups may be, for example, an amine group, a hydroxyl group, a carboxyl group, etc., and these protecting groups may be, for example, TW Greene and PGM Wuts, "P r 〇tective G r 〇upsi η 〇rganic Synthesis", 3rd edition, J 〇 h η Wiley & Sons, the protecting group described in 1999, can be suitably selected according to these reaction conditions. According to such a method, the protecting group can be introduced to react, and the protecting group can be removed as necessary or converted into a desired group to obtain a desired compound. The obtained compound of the present invention can be identified by standard analytical techniques such as elemental analysis, NMR, mass spectroscopy, and IR analysis, and its composition or purity can be analyzed. The starting materials or reagents used in the manufacture of the compounds of the present invention can be purchased from commercial suppliers or synthesized according to methods described in the literature. (Effects of the Invention) The compound of the present invention or a pharmacologically acceptable salt thereof exhibits excellent EPO productivity in a lineage using Hep3B cells in -27-200948788. When the compound of the present invention or a pharmacologically acceptable salt thereof is administered to a mammal (human, cow, horse, or pig, etc.) or a bird (chicken or the like), EP0 can be produced. Therefore, the compound of the present invention or a pharmacologically acceptable salt thereof can be used for the prevention and/or treatment of a disease caused by a low EPO, the blood storage of a patient for a predetermined surgery, and the like. Diseases caused by low EP0 can be used, for example, in anemia, especially renal anemia (dialysis period, preservation period), anemia of under-ripe children, anemia associated with chronic diseases, anemia associated with cancer chemotherapy, cancer anemia, and others can also be used for ischemia A disease such as a brain disease, a disease with low EP0, and a preventive and/or therapeutic agent for pathological use. [Embodiment] (Formulation of the Invention) A representative production method of the compound of the present invention is exemplified below. The method of the present invention is not limited to the following examples. The compound (1) of the present invention can be obtained by the following method. (First Project) The first project is a process for producing the compound (1) from the compound (2) described later. 200948788 The first project

〇

(2)

Pro3 1·2

(1) (3)

In the above, R1 to R3 are the same as the above-mentioned agreement, R4 is a substituted or unsubstituted aryl or heteroaryl group, or an aryl group or a heteroaryl group-substituted alkyl group, and R5 is a substituted or unsubstituted alkyl group or ring. An alkyl group, R6 and R7 are a substituted or unsubstituted hydrocarbon ring group or a heterocyclic group, 1118 and R1b are the above R1 or a substituent of the precursors -29-200948788, and R2a is a substituent of the above R2 or its precursor, Pro1 to Pro5 are protections of various functional groups selected by well-known methods (for example, Protective Groups in Organic Synthesis, 3rd ed.; Green, TW; Wuts, PGM, Eds.; John Wiley & Sons: New York, 1 999., etc.). base. Pro1 to Pro5 are as long as the stability is present in the reaction, and the unrestricted reaction is not limited. Pro1 is benzyl, Pro2 is tributyl, Pro3 is methyl or ethyl, Pro4 is third butoxycarbonyl, Pro5 is Methyl or ethyl. X1 is not particularly limited as long as it is a substituent which forms a leaving group together with the combined oxygen, and is preferably trifluoro.

Methionine. The following is a detailed description of each project. (1-1 Project) The 1-1 project is a process for producing the compound (3) from the compound (2) described later. The necessary reactions include: Ι-la engineering · Deprotection of protecting group Pro2 Ι-lb engineering: condensation reaction with amino acid or amine acid salt of formula H2NCH(R3)C〇2Pro3 1-lc engineering: The reaction at the 6-position hydroxyl group introduced into the leaving group (-0X1) Ι-ld works: the leaving group (-0X1) is converted into a substituent R2a2. If necessary, add: Ι-le project: Rla transforms to Rlb2 reaction. 1 -1 a to 1 -1 e works can be carried out before and after any operation, as long as it is the industry, it is easy to choose the order. (Ι-la Engineering) -30- 200948788 This project is to deprotect the protective base Pro2. According to the Pro2 used, for example, Protective Groups in Organic Synthesis, 3rd ed.; Green, TW; Wuts, PGM, Eds. John Wiley & Sons: New York, 19 99. The well-known methods described in the records are appropriate and subject to implementation. Here, a method of selecting a third butyl group for Pro2 and converting Pro2 into a hydrogen atom using a base in an inert solvent is described, but is not limited thereto. The solvent to be used is not particularly limited as long as it can dissolve the starting material to some extent, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; a halogen-based hydrocarbon such as dichloromethane or chloroform; diethyl ether or tetrahydrofuran; An ether such as 1,4-dioxane or 1,2-dimethoxyethane; an alcohol such as methanol, ethanol or 2-methylpropan-2-ol; an ester such as ethyl acetate or propyl acetate; a nitrile such as acetonitrile; a decylamine such as formamide or N,N-dimethylformamide; a bismuth such as dimethyl arsenate; a mixed solvent of any ratio of a plurality of organic solvents; and any combination with water a mixture of solvents and the like. The base to be used is not particularly limited as long as it is used as a base in a usual reaction, and Q may be an organic base such as triethylamine; an alkali metal carbonate such as sodium carbonate; an alkaline earth metal carbonate such as cesium carbonate; Alkali metal hydrogencarbonates such as potassium: alkaline earth metal hydrogencarbonates such as calcium hydrogencarbonate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; and alkaline earth metal hydroxides; An alkali metal phosphate such as potassium. The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -10 ° C to 150 ° C, preferably 10 ° C to 90 ° C. The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 1 minute to -31 to 200948788 for 24 hours, preferably from 10 minutes to 6 hours. After the completion of the reaction, the objective compound of the reaction can, for example, concentrate the reaction mixture, add water and An organic solvent which is not mixed with ethyl acetate or the like, and after washing with water, the organic layer containing the objective compound is separated, dried over anhydrous magnesium sulfate, and then evaporated. The obtained compound can be more refined if necessary by a usual method such as recrystallization, reprecipitation, gel column chromatography or the like. (Ι-lb Engineering) Λ This project is the engineering of condensing a compound of formula (2) with an amino acid or an amine acid salt of the formula H2NCH(R3)C〇2Pro3 ^ in an inert solvent. The use of a condensing agent is carried out in the presence or absence. The solvent to be used is not particularly limited as long as it can dissolve the starting material to some extent, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; a halogen-based hydrocarbon such as dichloromethane or chloroform; An ester such as propyl acetate; an ether such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane; an alcohol such as methanol, ethanol or 2-methylpropan-2-ol; Nitriles such as acetonitrile; guanamines such as formazan Q amine, hydrazine, hydrazine-dimethylformamide; sub-millings such as dimethyl sulfoxide; mixed solvents of any ratio of plural organic solvents, and water Mixed solvent of any ratio, etc. The base to be used is not particularly limited as long as it is a normal reaction, and is preferably an organic base such as triethylamine, diisopropylethylamine, 4-methylmorpholine, methylpyridine or pyridine; sodium carbonate or the like. Alkali metal carbonates; alkaline earth metal carbonates such as barium carbonate; alkali metal hydrogencarbonates such as potassium hydrogencarbonate; calcium hydrogencarbonate-32-200948788; alkaline earth metal hydrogencarbonates; alkali metal hydrogen such as sodium hydroxide Oxide: alkaline earth metal hydroxides such as water oxychloride; alkali metal phosphates such as tripotassium phosphate. The condensing agent used is only for the user who is a condensing agent for forming a guanamine bond (for example, Nanben Masaichi, Experimental Science Lecture IV; Japanese Chemical Society; Jiushan, 1 990. or Quanwu Xinfu, etc. And experiment; nine good, 〇

1 9 85. The method described in the above), there is no limit, preferably 0-benzotriazole-N, N, N', N'-tetramethyl urea hexafluorophosphate (HBTU), or 2- (1Η-benzotriazol-1-yl)-1,1,3,3-tetramethylurea-tetrafluoroborate (TBTU), 1-(3-dimethylaminopropyl)-3 -ethylcarboxylimine diimide hydrochloride (EDCI), 4·(2-{[(cyclohexylamido)methylene]amino}ethyl-4-methylmorpholin-4-key pair Tosylate (CMC), dicyclohexylcarboxy quinone diimide (DCC), 1,1'-carbonyl bis(1H-imidazole) (CDI), (1H-benzotriazol-1-yloxy) (Tripyrrolidin-1-yl) hexafluorophosphate (PyBOP), bromo(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (PyBrOP), 4-(4,6-dimethoxy-1 , 3,5-three tillage-2-yl)·4-methylmorpholinyl chloride (DMT-MM), 2-chloro-4,6-dimethoxy-l,3,5-three tillage (DMT) Further, it may be added as an additive to 1-hydroxybenzotriazole (oxime), hydrazine, hydrazine-dimethylaminopyridine, etc. The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -10 ° C to 150 ° C, preferably 0 ° C to 100 ° C. The reaction time varies depending on the starting compound, reagent, etc., usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours. After the reaction is completed, the target compound of the reaction can be, for example, concentrated from the reaction mixture -33-200948788, and added with an organic solvent such as water and ethyl acetate, and washed and separated. The organic layer containing the objective compound is dried with anhydrous magnesium sulfate or the like, and the solvent is distilled off. The obtained compound can be further purified by a usual method, for example, recrystallization, reprecipitation, silica gel column chromatography, etc. (1 1 c Engineering) This project is a process for introducing a hydroxyl group into a leaving group (-OX1) at the 6-position, and reacting with a chlorine or an acid anhydride in the presence or absence of a base in an inert solvent. The solvent used does not hinder the reaction. If the starting material can be dissolved to some extent, it is not limited, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; a halogen hydrocarbon such as dichloromethane or chloroform; an ester such as ethyl acetate or propyl acetate; And ethers such as tetrahydrofuran '1,4-dioxane and 1,2-dimethoxyethane; nitriles such as acetonitrile; guanamines such as formamide and N,N-dimethylformamide; Borax, such as yam, and other organic solvents The ruthenium chloride or acid anhydride used in the mixed solvent of the ratio is not particularly limited as long as it is a ruthenium chloride or an acid anhydride having a -OX1 group which is a known decarburization group X1, and is preferably a substituted or unsubstituted alkyl group such as trifluoromethanesulfonic anhydride. a sulfonic acid anhydride or an aryl sulfonic acid anhydride; a substituted or unsubstituted alkane sulfonium chloride or an arylsulfonyl chloride such as methylsulfonium chloride or p-toluenesulfonyl chloride; a substituted or unsubstituted alkylphosphonium chloride or an arylphosphonium chloride The base to be used is not particularly limited as long as it is a normal reaction as a base user, and is preferably triethylamine, diisopropylethylamine, 4-methylmorpholine, methylpyridine, pyridyl-34-200948788, etc. Organic alkalis; base metal carbonates such as sodium carbonate; alkaline earth metal carbonates such as carbonic acid planing; alkali metal hydrogencarbonates such as potassium hydrogencarbonate; alkaline earth metal hydrogencarbonates such as calcium hydrogencarbonate; Alkali metal hydroxides; hydroxide alkaline earth metal hydroxides; alkali metal phosphates such as tripotassium phosphate. The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -10 ° C to 150 ° C, preferably -80 ° C to 40 ° C. The reaction time varies depending on the starting compound, the reagent, and the like, and is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours. After the completion of the reaction, the objective compound of the reaction can, for example, concentrate the reaction mixture, add water, ethyl acetate, etc. The organic solvent which is not mixed, and after washing with water, the organic layer containing the objective compound is separated, dried with anhydrous magnesium sulfate or the like, and the solvent is distilled off. The obtained compound can be more refined if necessary by a usual method such as recrystallization, reprecipitation, gel column chromatography or the like. 〇 (ι-id project) This project is a project to convert the off-base (-OX1) into a substituent R2a. Where R 2a is an alkyl or alkenyl group, an alkyl boron compound or an alkenyl boron is present in the presence or absence of a base in an inert solvent in the presence or absence of a metal catalyst in the presence or absence of an additive Compound reaction is carried out (Ι-ldl engineering). Further, in the case where R2a is a methylthioalkyl group, a metal salt of methyl mercaptan or methyl mercaptan is reacted in the presence or absence of a base in an inert solvent (1-ld2 engineering). On the one hand, in the case of difluoromethyl or fluoromethyl, the compound which is introduced into the methyl group by R2a obtained as a result of the above-mentioned -1 -1 d 1 project, after the action with a base in an inert solvent, and the electrophilic fluorination The reagent reaction was carried out (1-1 d3 project). (1 -1 d 1 project) This project is to convert the de-based group (-OX1) into &2& into an alkyl or alkenyl group. 'In the presence or absence of a base in an inert solvent, there is an additive. The alkyl boron compound or the alkenyl boron compound is reacted in the presence or absence of a metal catalyst in the presence or absence of a metal catalyst. Such reaction conditions can be, for example, Zou, G.; Reddy, YK; Falck, JR Tetrahedron Lett. 2001, 42, 72 1 3., or Molander, GA; Yun, C.-S. Tetrahedron 2002, 58, 1465. Tsuji, J. Palladium Reagents and Catalysts;

John Wiley & Sons: England, 2004. and Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004. The well-known methods described in the paper are suitable for selection. Its implementation. Suitable conditions are described below, but are not limited thereto. The solvent to be used is not particularly limited as long as it can dissolve the starting material to some extent, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; a halogen hydrocarbon such as dichloromethane or chloroform; and ethyl acetate; And esters such as propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol and 2-methylpropan-2-ol a nitrile such as acetonitrile; a guanamine such as formamide or N,N-dimethylformamide; a sub-mill of dimethyl sulfoxide; a mixed solvent of any ratio of a plurality of organic solvents, and a mixture with water Mixed solvent of any ratio, etc. The base to be used is not particularly limited as long as it is a normal reaction, and is preferably an organic base such as pyridine; an alkali metal carbonate such as potassium carbonate; an alkaline earth metal carbonate such as carbonic acid planing; and hydrogen carbonate. Alkali metal hydrogencarbonates such as potassium; alkaline earth metal hydrogencarbonates such as calcium hydrogencarbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as water oxychloride; Metal salts; metal alkoxides such as sodium t-butoxide or potassium t-butoxide. The additive to be used is not particularly limited as long as it is used in a known method, and is preferably a metal oxide such as silver oxide or aluminum oxide; triphenylphosphine, tri-tert-butylphosphine, trimethylcyclohexylphosphine, or tris(o-tolylhydrazyl). Phosphine, diphenylphosphinoferrocene, 2_dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (S-PHOS), 2-dicyclohexylphosphino -2' ,4' ,6' -triisopropyl-1,1,-biphenyl (X-PHOS), 2,2,-linked (diphenylphosphino)-1,1'-binaphthyl (BINAP Phosphines such as phosphines; triphenylphosphine oxides; metal salts such as lithium chloride, potassium fluoride, and fluorinated planing; ammonium salts such as tetrabutylammonium bromide; These can be used in combination in any ratio. The metal catalyst used is not limited as long as it is used in a known method, and is preferably ruthenium (triphenylphosphine) palladium, bis(tri-tributylphosphine) palladium, palladium acetate 2, palladium diphenylphosphonium dichloride. Ferrocene complex, 2 palladium chloride benzonitrile complex, 2 palladium chloride acetonitrile complex, bis(dibenzylideneacetone) palladium, ginseng (dibenzylideneacetone) dipalladium, double [ 1,2-bis(diphenylphosphino)ethane]palladium, 3-chloropyridine [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium, palladium-activated carbon Palladium catalyst. The alkyl boron compound and the alkenyl boron compound to be used are not particularly limited as long as they are used as a known reactant. When R 2a is an alkyl group, it may be methyl boric acid, methyl borate or trifluoro(methyl) borane metal. Salt, ethyl boric acid, ethyl borate or -37- 200948788 Ethyl difluoroboron metal salt, etc., when R2a is a cyclopropyl group, it may be cyclopropylboronic acid, cyclopropyl borate or cyclopropyl (trifluoro) a borane-like metal salt or the like, and in the case where R2» is an alkenyl group, it may be vinylboronic acid or 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborane. Vinyl borate, vinyl trifluoroborane metal salt, allyl boric acid, allyl borate or allyl (trifluoro)-borane metal salt. The ester of the alkyl borate, the metal of the trifluoro(alkyl)borane metal salt, the ester of the alkenyl borate, and the metal of the trifluoro(alkenyl)borane metal salt are as long as Known compounds are known or synthesized by known methods, and are not limited. The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -10 ° C to 200 ° C, preferably 0 ° C to 150 ° C. The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 5 minutes to 48 hours, preferably from 10 minutes to 12 hours. After the completion of the reaction, the target compound of the reaction can be, for example, concentrated, and an organic solvent such as water or ethyl acetate is added, and after washing with water, the organic layer containing the objective compound is separated, dried over anhydrous magnesium sulfate, and evaporated. Obtained from the solvent. The obtained compound can be more refined if necessary by a usual method such as recrystallization, reprecipitation, gel column chromatography or the like. When R2a is an alkenyl group, an alkyl group corresponding to R2 can be induced by performing a hydrodecomposition reaction according to the l-2al process described later. (l-ld2 Engineering) -38- 200948788 This project is a project to convert a detached group (-OX1) into a methylthioalkyl group of R2a. In the presence or absence of a base in an inert solvent, methyl mercaptan is used. Or a metal salt of methyl mercaptan is reacted for execution. The solvent to be used can dissolve the starting material to some extent as long as it does not inhibit the reaction, and it is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; a halogen-based hydrocarbon such as dichloromethane or chloroform; Esters such as propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; Initrile such as acetonitrile; formamide, N,N-dimethyl An amine such as carbamide; an alcohol such as methanol or ethanol; an anthracene such as dimethyl hydrazine; a mixed solvent of any ratio of a plurality of organic solvents; and a mixed solvent of any ratio with water. The metal to be used as the metal salt of methyl mercaptan is not particularly limited, and is preferably an alkali metal such as sodium or an alkaline earth metal such as magnesium. The base to be used is not particularly limited as long as it is a normal reaction, and is preferably an organic base such as azoidine; an alkali metal ruthenium carbonate such as sodium carbonate or potassium carbonate; an alkaline earth metal carbonate such as cesium carbonate; An alkali metal hydrogencarbonate Q salt such as potassium hydrogen; an alkaline earth metal hydrogencarbonate such as calcium hydrogencarbonate; an alkali metal hydroxide such as sodium hydroxide; an alkaline earth metal hydroxide such as a water-soluble planer; Alkali metal phosphates; metal alkoxides such as potassium butoxide. The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -10 ° C to 150 ° C, preferably 0 ° C to 100 ° C. The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 5 minutes to 48 hours, preferably from 10 minutes to 12 hours. -39-200948788 After the reaction is completed, the objective compound of the reaction can, for example, concentrate the reaction mixture to add water and An organic solvent which is not mixed with ethyl acetate or the like, and after washing with water, the organic layer containing the objective compound is separated, dried with anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain a compound obtained by a usual method such as recrystallization or reprecipitation. , 矽 rubber column chromatography, etc. to be more refined. (l-ld3 project)

This project is to convert the methyl group introduced as R2a into a difluoromethyl group or a fluoromethyl group in the above-mentioned Ι-ldl engineering compound, in an inert solvent, after alkali action, and electrophilic fluorination test The drug reacts to be carried out. These can appropriately adjust the equivalent number of the base and the electrophilic fluorinated reagent to prepare the compound of interest.

The solvent to be used is not particularly limited as long as it can dissolve the starting material to some extent, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; a halogen-based hydrocarbon such as dichloromethane or chloroform; diethyl ether or tetrahydrofuran; Ethers such as 1,4-dioxane and 1,2-dimethoxyethane; nitriles such as acetonitrile; decylamines such as formamide, hydrazine, hydrazine-dimethylformamide; An isoindole; a mixed solvent of any ratio of a plurality of organic solvents, and the like. The base to be used is not particularly limited as long as it is a normal reaction, and is preferably an organic metal ruthenium such as diisopropylamide or sodium hexamethyldiazide, or an organic compound such as a third butyl lithium. An electrophilic fluorinated reagent for use in a metal compound, a hydrogenation metal such as potassium hydride, or the like is known (for example, Baudoux, J.; -40-200948788)

Cahard, D. Electrophilic Fluorination with NF Reagent. In Organic Reaction; Overman, LE, Ed.; John Wiley & Sons, Inc.: New Jersey, 2007; Vol.69: Chapter 2. Synthesis and function of fluorine compounds; Ishikawa Yannan; CMC company: Tokyo, 1987.) used in the test drug, there is no limit, it should be N-fluorobenzenesulfonimide (NFSI). The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -100 ° C to 100 ° C, preferably -80 ° C to 50 ° C.

The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 5 minutes to 48 hours, preferably from 10 minutes to 12 hours. After the completion of the reaction, the target compound of the present reaction can be, for example, concentrated, and an organic solvent such as water and ethyl acetate is added. After washing with water, the organic layer containing the objective compound is separated, dried over anhydrous magnesium sulfate and evaporated. And got it. The obtained compound can be more refined if necessary by a usual method such as recrystallization, reprecipitation, gel column chromatography or the like. (1 -1 e project) This project is a project to convert Rla to Rlb. The synthesis method differs depending on the type of hydrocarbon ring in the Q1 or Q2 part, so it can be divided into the following cases. (1) Rla' includes an aromatic hydrocarbon ring Q1 or Q2 having a halogen atom or a -0X1 group, and (1) when Q1 or Q2 is directly introduced into the substituent R4 (the Ι-lel project is introduced by an oxygen atom) In the case of the base R5 (1_le2 project) (2) As Rla' includes a naphthenic ring structure, (i) when the cycloalkyl ring is introduced into the substituent R6 by an oxygen atom -41 - 200948788 (1-1 e4 project) (ii) When a substituent R7 is introduced by a nitrogen atom (1-1 e5 project) The reaction necessary for (1) of (Ι-le engineering) is: Ι-lel engineering: introduction reaction of substituent R4 1-1 e2 works: a reaction with a light-emitting group of an alcohol having a substituent R5. Here, as Rla, there is a case where a phenyl group having a halogen atom or a -OX1 group is removed from the group, but is not limited thereto. (Ι-lel engineering) This project is for the manufacture of a compound of formula (5) or (7) under the presence of a metal catalyst in the presence or absence of a base in the presence or absence of an additive in the absence of a base in an inert solvent, in the presence or absence of an additive. a substituted or unsubstituted aryl boronic acid or a heteroaryl boronic acid or an alkyl boronic acid, which is inversely related to the compound of the formula (4) or (6) The reaction conditions for the purposes of the example Tsuji, J Palladium Reagents and Catalysts; John Wiley & Sons:... England, 2004 or Jiang, L.

Buchwald, SL Palladium-Catalyzed Aromatic Carbon-Ni torogen Bond Formation. In Metal - Catalyzed Cross-Coupling Reactions ; de Meijere, A·, Diederich, F_, Eds.; Wiley-VCH: Weinheim, 2004; Chapter 13. The well-known method is suitable for selection and is implemented according to it. The following suitable conditions are described herein, but are not limited thereto. The solvent to be used is not particularly limited as long as it can dissolve the starting material to some extent, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; a halogen-based hydrocarbon such as dichloromethane or chloroform; Esters such as propyl acetate; -42- 200948788 ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; methanol, ethanol, 2-methylpropan-2-ol Alcohols; nitriles such as acetonitrile; decylamines such as formamide, N,N-dimethylformamide; sub-mills such as dimethyl sulphide; mixed solvents of any ratio of plural organic solvents, and A mixed solvent or the like in any ratio with water. The base to be used is not particularly limited as long as it is a normal reaction, and is preferably an organic base such as pyridine; an alkali metal carbonate such as potassium carbonate; an alumina metal carbonate such as carbonic acid planing; potassium hydrogencarbonate or the like. Alkali metal hydrogencarbonates; alkaline earth metal hydrogencarbonates such as barium hydrogencarbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as water-soluble planers; alkali metal phosphates such as tripotassium phosphate a metal alkoxide such as sodium tributoxide or potassium t-butoxide; an organometallic guanamine such as lithium diisopropyl guanamine or sodium hexamethyldiazide; a third butyl lithium Such as an organometallic compound; a hydrogenated metal such as potassium hydride. The additive to be used is not particularly limited as long as it is used in a known method, and is preferably a metal oxide such as silver oxyhydroxide or aluminum oxide; triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, or tri(o-tolylhydrazyl). Phosphine, diphenylphosphinoferrocene, 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (S-PHOS), 2-dicyclohexylphosphino -2' ,4' ,6' -triisopropyl-1,1' _biphenyl (X-PHOS), 2,2,-bis(diphenylphosphino)-1, fluorene-binaphthyl (BINAP) Such as phosphines; phosphine oxides such as triphenylphosphine oxide; metal salts such as lithium chloride, potassium fluoride, and fluorinated planing; ammonium salts such as tetrabutylammonium bromide. These can be used in combination in any ratio. The metal catalyst used is not limited as long as it is used in a known method, and is preferably -43-200948788 as ruthenium (triphenylphosphine) palladium, bis(tri-tributylphosphine) palladium, palladium acetate 2, palladium chloride Diphenylphosphinoferrocene complex, 2 palladium chloride benzonitrile complex, 2 palladium chloride acetonitrile complex, bis(dibenzylideneacetone)palladium, ginseng(dibenzylideneacetone)dipalladium , bis[1,2-bis(diphenylphosphino)ethane]palladium, 3-chloropyridine [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium, palladium - a palladium catalyst such as activated carbon. The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -10 ° C to 200 ° C, preferably 〇 ° C to 150 ° C. The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 5 minutes to 48 hours, preferably from 10 minutes to 12 hours. After the completion of the reaction, the target compound of the present reaction can be, for example, concentrated, and an organic solvent such as water and ethyl acetate is added. After washing with water, the organic layer containing the objective compound is separated, dried over anhydrous magnesium sulfate and evaporated. And got it. The obtained compound can be further refined if necessary by a usual method such as recrystallization, reprecipitation, grit column chromatography or the like.

This reaction is carried out in a carbon monoxide gas atmosphere to obtain a compound (8) having a carbonyl group interposed therebetween. (l-le2 Engineering) This project is a process for the manufacture of a compound of formula (10). Substituted or unsubstituted cycloalkyl or substituted alkane in the presence of an azo compound and a phosphine in an inert solvent under a nitrogen atmosphere. The base alcohol is reacted with a delayed reaction of the compound of the formula (9). The solvent to be used is not particularly limited as long as it does not inhibit the reaction, and the starting material is dissolved to some extent - 44 - 200948788, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene: a halogen-based hydrocarbon such as dichloromethane or chloroform; An ether such as diethyl ether, tetrahydrofuran, M-dioxane or 1,2-dimethoxyethane. The reagent to be used for the photo-delay reaction is not particularly limited as long as it is a reagent which can be used for the usual photo-delay reaction, and is preferably an azodicarboxylic acid such as diethyl azodicarboxylate or diisopropyl azodicarboxylate. An azo compound such as a dihomoalkyl ester or a heterocyclic azodicarbonyl group such as M'-(azodicarbonyl)dipiperidine; a triarylphosphine such as triphenylphosphine or a trihalophosphine such as tributylphosphine The combination of the phosphines is more preferably a combination of diethyl azobisdicarboxylate and triphenylphosphine or a combination of 1,1'-(azodicarbonyl)dipiperidine and tributylphosphine. The reaction temperature varies depending on the starting compound and the reaction reagent, and is carried out at -50 ° C to 100 ° C, preferably from -10 ° C to 60 ° C. The reaction time varies depending on the reaction temperature, the starting compound, the reaction reagent or the solvent to be used, and is usually from 10 minutes to 48 hours, preferably from 30 minutes to 24 hours. After the end of the Q reaction, the target compound of the reaction can, for example, be reacted. The mixture is concentrated, and an organic solvent which is not mixed with water and ethyl acetate is added, and after washing with water, the organic layer containing the objective compound is separated, dried over anhydrous magnesium sulfate, and then evaporated. The obtained compound can be more refined if necessary by a usual method such as recrystallization, reprecipitation, gel column chromatography or the like. The reaction necessary as (2) of (l-le engineering) is l-le4 engineering: reaction with a hydroxyl group having a substituent R6 -45- 200948788 1-1 e5 engineering: with an amine having a substituent R7 reaction. Further, when necessary, the l-le3 project: the reduction reaction of the compound (11) is used herein as Rla and has a substituted cyclohexyl group, but is not limited thereto. (l-le3 Engineering) This project is a project to reduce the carbonyl group of formula (11) to a hydroxyl group.

The solvent to be used may be, for example, an aromatic hydrocarbon such as benzene, toluene or xylene; a halogenated hydrocarbon such as dichloromethane or chloroform; an ether such as diethyl ether, tetrahydrofuran, 1, cardiodioxane or 1,2-dimethoxyethane; An alcohol such as methanol, ethanol or 2-methylpropan-2-ol; and a mixed solvent of an alcohol and a halogenated hydrocarbon, preferably methanol, ethanol, tetrahydrofuran or a mixed solvent of the above alcohol and dichloromethane. The reagent to be used is not particularly limited as long as it is a reagent for the reaction of reducing a carbonyl group into a hydroxyl group, and may be, for example, a boron-containing hydrazine reagent, a sodium borohydride, a diborane, or a hydrogenated tri(second butyl)borosilicate. The compound is preferably sodium borohydride or hydrogenated tri(secondary butyl)borohydride.

The reaction temperature varies depending on the starting compound and the reaction reagent, and is carried out at -100 ° C to 100 ° C, preferably from -7 8 ° C to 50 ° C. The reaction time varies depending on the reaction temperature, the starting compound, the reaction reagent or the solvent to be used, and is usually from 10 minutes to 12 hours, preferably from 30 minutes to 5 hours. After the completion of the reaction, the target compound of the reaction can be, for example, concentrated, and an organic solvent such as water or ethyl acetate is added. After washing with water, the organic layer containing the objective compound is separated, dried over anhydrous magnesium sulfate, and then evaporated. - 200948788 Derived from solvent. The obtained compound can be further refined if necessary by a usual method such as recrystallization, reprecipitation, gel column chromatography or the like. (l-le4 project) This project is for the construction of the compound of the formula (13) and the imitation l-le2 project (l-le5 project)

This work is a process for the production of a compound of the formula (14) by a reductive amination process of a substituted or unsubstituted cycloalkylamine or an aromatic amine with a compound of the formula (11) under a nitrogen atmosphere. The solvent to be used is not particularly limited as long as it can dissolve the starting material to some extent, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; dichloromethane, chloroform, 1,2-dichloroethane, etc. Halogen-based hydrocarbons; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols and alcohols such as methanol, ethanol, and 2-methylpropan-2-ol The mixed solvent with the halogenated hydrocarbon is preferably 1,2-dichloroethane, methanol, ethanol, tetrahydrofuran, or a mixed solvent of the above alcohol and dichloromethane. As the reaction reagent, a reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triethoxy hydride hydride may be used, and sodium triethoxy hydride hydride is preferably used. The reaction temperature varies depending on the starting compound and the reaction reagent, and is carried out at -50 ° C to 100 ° C, preferably from 0 ° C to 50 ° C. The reaction time varies depending on the reaction temperature, the starting compound, the reaction reagent or the solvent to be used, and is usually from 10 minutes to 24 hours, preferably from 30 minutes to -47 to 200948788 for 1 hour. After the completion of the reaction, the target compound of the present reaction can be, for example, concentrated, and an organic solvent such as water and ethyl acetate is added. After washing with water, the organic layer containing the objective compound is separated, dried over anhydrous magnesium sulfate and evaporated. And got it. The obtained compound can be more refined if necessary by a usual method such as recrystallization, reprecipitation, gel column chromatography or the like. (1-2 Project) The 1-2 project is a process for producing a compound of the formula (1) from a compound of the formula (3). The necessary reactions are: l-2a project: deprotection reaction of protecting group Pro1 1-2b engineering: deprotection reaction of protecting group Pro3, if necessary, can be added: l-2c engineering: conversion of Rlb to R1. The 1-2a to 1-2c projects can also be implemented before and after, as long as the operator can easily select the order. (l-2a Engineering) This project is a deprotection project for the protection group Pro1, which will be used according to Pro1, for example, Protective Groups in Organic Synthesis, 3rd ed.; Green, TW; Wuts, PGM, Eds.; John Wiley & Sons: The well-known methods described in New York, 1999, etc. are appropriately selected and implemented according to them. The suitable Pro1 is a method of selecting a benzyl group, converting the Pro1 into a hydrogenogen 200948788 by using a catalyst under the action of a hydrogen atmosphere, in an inert solvent, in the presence or absence of an additive, or in the absence of an additive (l-2al), hydrogen. A method of converting Pro1 into a hydrogen atom by using a catalyst in the presence of an organic compound capable of becoming a hydrogen source in an atmosphere of nitrogen or argon, in an inert solvent, in the presence or absence of an additive, or in the absence of an additive (1) -2a2) or a method (l-2a3) which converts Pro1 into a hydrogen atom with an appropriate acid in an inert solvent, but is not limited to these. (l-2al Engineering) This project is a project in which Pro1 is converted into a hydrogen atom by a catalyst under the presence of an additive in a hydrogen atmosphere or an inert solvent in the presence or absence of an additive. The solvent to be used in the hydrazine is not particularly limited as long as it does not inhibit the reaction, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; a halogen-based hydrocarbon such as dichloromethane or chloroform; And esters such as propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol and ethanol; nitriles such as acetonitrile; and formazan. Anthracene such as N,N-dimethylformamide; an anthracene such as dimethyl hydrazine: a mixed solvent of any ratio of a plurality of organic solvents, and a mixed solvent with an arbitrary ratio with water. 〇 The additive used is a user of hydrochloric acid equal to the known method, and is not limited. The metal catalyst to be used is a user of a known method, and is not limited, and is preferably palladium-activated carbon, stilbene (triphenylphosphine) ruthenium chloride or palladium hydroxide. The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -loot to 150 ° C, preferably 0 ° C to 100 ° C. The reaction time varies depending on the starting compound, the reagent, and the like, and is usually from 5 minutes to 24 hours, preferably from 10 minutes to 6 hours. After the completion of the reaction, the insoluble matter was filtered, and the filtrate was distilled under reduced pressure. The resulting residue is purified by a usual method such as recrystallization, distillation, silica gel column chromatography or the like. When R2a is an alkenyl group, it may be induced to a corresponding alkyl group as described above. (l-2a2 Engineering) This project uses a catalyst in the presence of an organic compound capable of becoming a hydrogen source in a nitrogen or argon atmosphere, in an inert solvent, in the presence or absence of an additive, or in the absence of an additive. A project that converts Pro1 into a hydrogen atom.

The solvent to be used is not particularly limited as long as it can dissolve the starting material to some extent, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; a halogen-based hydrocarbon such as dichloromethane or chloroform; Esters such as propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; alcohols such as methanol and ethanol; nitriles such as acetonitrile; formamide, N , N_: a guanamine such as methylmethamine; an anthracene such as dimethyl selenide; a mixed solvent of any ratio of a plurality of organic solvents; and a mixed solvent with an arbitrary ratio with water.

In the case of a non-hydrogen atmosphere, the organic compound of the hydrogen source used is a formic acid or the like, and there is no limitation on the user. The additive used is a user of hydrochloric acid equal to the method of the known method, and is not limited. The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually _10 (rc to 150 ° C ' is preferably -78 ° C to 10 CTC. The reaction time varies depending on the starting compound, the reagent, etc., usually 5 minutes to 24 hours. The hour is preferably 1 to 6 hours. After the reaction is completed, the reaction solution is extracted with an organic solvent such as dichloromethane or ethyl acetate, and the organic layer is dried by the usual operation, -50-200948788, and then concentrated. The residue obtained is purified by a usual method such as recrystallization, distillation, silica gel column chromatography, etc. (l-2a3 Engineering) This is a method for converting Pro1 into a hydrogen atom with an appropriate acid in an inert solvent. As long as the reaction can be dissolved to some extent without hindering the reaction, it is not limited, and is preferably an aromatic hydrocarbon such as benzene, toluene or xylene; a halogen-based hydrocarbon such as dichloromethane or chloroform; and ethyl acetate or acetonitrile. Esters such as esters; ethers such as hydrazine ether, tetrahydrofuran, 1,4-dioxane, 1,2. dimethoxyethane; alcohols such as methanol and ethanol; nitriles such as acetonitrile: formamide, hydrazine, Indoleamines such as hydrazine-dimethylformamide; An anthracene such as dimethyl sulfite; a mixed solvent of any ratio of a plurality of organic solvents; a mixed solvent with an arbitrary ratio with water, etc. The acid to be used is not particularly limited as long as it is usually used as an acid user. Mineral acid such as hydrochloric acid or sulfuric acid; Lewis acid such as boron trifluoride, boron trichloride, boron tribromide or trimethylsulfonium iodide; organic acid such as trifluoroacetic acid, etc. Q reaction temperature is based on raw material compound and reagent The difference is usually -locrc to 150 ° C, preferably -78 ° C to 100 ° C. The reaction time varies depending on the starting compound, the reagent, etc., usually 5 minutes to 24 hours, preferably 1 〇 After the reaction is completed, water or hydrochloric acid is added, and the organic substance is extracted with an organic solvent such as dichloromethane or ethyl acetate, or the reaction mixture is concentrated under reduced pressure, and then a base such as sodium hydrogen carbonate aqueous solution is added to dichloromethane and ethyl acetate. The organic layer is extracted with an organic solvent such as an ester, and the organic layer is dried and concentrated by a usual operation, and the obtained residue is purified by a usual method such as recrystallization, distillation, silica gel column chromatography, etc. (l-2b) Project is The protection of the protection base Pro3 can be carried out in the same way as the 1-la project. (l-2c engineering) This project is a project that converts Rlb into R1, and can be executed as a project. (2nd project) 2nd project 2 Engineering is the manufacturing process of the aforementioned compound (2).

In the above, Rla is a substituent of the above R1 or a precursor, Pro1 and Pro2 are a protecting group of the above functional group, and Pro6 is a known method (for example, Protective Groups in Organic Synthesis, 3rd ed.; Green, TW; Wuts, PGM, Eds.; John Wiley & Sons: New York, 1 999., etc.) The protecting group of each functional group is selected, and the reaction is stable, and the reaction is not hindered, and there is no limitation, and it is preferably a methyl group. The compound of the formula (2) can be subjected to a known method ((i) a substituted ethylenimine (15) and a 2-alkoxy-3-oxysuccinate diester (16) prepared by a conventionally known method. The method of condensation in the presence of: Dreher, SD; Ikemoto, N.; Gresham, V.; Liu, J.; Dormer, PG; Balsells, J.; Mathre, D. 200948788; Novak.TJ; Armstrong III, J. ο. Tetrahedron Lett. 2004, 45, 6023. or (ii) Method for the condensation of N-hydroxy substituted ethylimidoamines (17) with acetylene monodecanoate (18): Culbertson, TPJ Heterocycl. Chem. 1979, 16, 1423-1424.) or synthesized by a method known in the art. The reaction product obtained by the above respective production methods can be purified by isomerization of various solvates such as a free compound, a salt thereof or a hydrate. Salt can be produced by conventional salt treatment. The separation and purification can be carried out by usual chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography. The various isomers can utilize the difference in physicochemical properties between the isomers and are routinely separated. For example, optical isomers can be separated by general optical division methods such as separate crystallization or chromatography. Further, optical isomers can also be produced from suitable optically active starting materials. The preparation containing the compound of the present invention as an active ingredient can be prepared by using a carrier or an excipient or other additives which are usually used for the formulation of the Q. Injectable tablets, nine doses, capsules, granules, powders, liquids, etc., or intravenous, intramuscular injections, suppositories, transdermal agents, nasal sprays or inhalants Oral cast with any form. The amount of administration can be appropriately determined depending on the symptoms, the age of the subject, the sex, etc., and is usually administered 0.001 mg/kg to 100 mg/kg per day for oral administration. 1 or 1 to 6 back cast. In the case of intravenous administration depending on the symptoms, it is usually from 0.01 mg/kg to 10 mg/kg per adult, and from 1 to 53 to 200948788, one to several times. The solid composition to be orally administered according to the present invention may be a tablet, a powder, a granule or the like. The active material of one or more of these solid compositions is mixed with at least one inert excipient such as lactose, mannitol, glucose or the like. The composition may contain an inert additive such as a slip agent such as magnesium stearate or a breaker such as sodium carboxymethyl starch or a dissolution aid according to a usual method. A lozenge or nine doses may also be coated with a sugar-coated or stomach-soluble or enteric coating if necessary. The liquid composition to be administered orally contains a pharmaceutical acceptable emulsion, a liquid, a suspending agent, a syrup, an elixir, and the like, and an inert solvent generally used, for example, purified water or ^ethanol. The composition may contain, in addition to the inert solvent, a compatibilizing agent such as a solubilizing agent, a wetting agent or a suspending agent, a sweetener, a flavoring agent, a fragrance, and a preservative. Injectables for parenteral administration contain sterile aqueous or non-aqueous liquids,

Suspending agent, emulsion. The aqueous solvent may be, for example, distilled water for injection and physiological saline. The non-aqueous solvent may, for example, be a vegetable oil such as propylene glycol, polyethylene glycol or olive oil, an alcohol such as ethanol, or a polysorbate 80 (Japanese Pharmacopoeia). These compositions may further contain an isotonic agent, a preservative, a wetting agent, an emulsifier, a dispersing agent, a stabilizer, and a dissolution aid. These can be sterilized, for example, by filtration of a bacteria-retaining filter, mixing or irradiation of a bactericide. These can also be used to make sterile solid compositions which are dissolved, suspended in sterile water or sterile injectable solutions prior to use. [Examples] The present invention is described in more detail below with reference to Examples, Examples, and Test Examples, but the scope of the present invention is not limited thereto. Reference Example 1 (ί[5-(Benzyloxy)-2-(4-bromobenzyl)-6-hydroxypyrimidin-4-yl]carbonyl}amino)ethyl acetate

(1) 2-(4-Bromophenyl)ethylimidate ethyl ester hydrochloride Ο

Nh hci (4-bromophenyl)acetonitrile (35.0 g, 178 mmol) was dissolved in ethanol (80 mL), cooled to 0 ° C, and stirred for 2 hours while blowing hydrogen chloride. The reaction mixture was combined with diethyl ether (EtOAc) (EtOAc) lH-NMR (500MHz, CDC13) <5: 7.49 (2H, d, J = 8 Hz), 7.33 (2H, d, J = 8 Hz), 4.61 (2H, q, J = 7 Hz), 4.01 ( 2H, s), 1.45 (3H, t, J = 7 Hz) » (2) 2-(4-bromophenyl)ethylenimineamine hydrochloride

NH HCI Ethyl 2-(4-bromophenyl)ethylimidate hydrochloride (2.0 g, 7.2 mmol) was dissolved in ethanol (10 mL), methanol (5 mL), and ammonium carbonate (2.0 g). Stir at room temperature for 17 hours. After ethanol was added to the reaction mixture, and the residue was evaporated. -55- 200948788 lH-NMR (500MHz, DMSO-d6) δ 7.59 (2H, d, J = 8 Hz), 7.44 (2H, d, J = 8 Hz), 3.72 (2H, s). (3) 3-(benzyloxy)-2-(4-bromobenzyl)-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester

After a solution of dibutylamine (9.5 mL, 68 mmol) in tetrahydrofuran (50 mL) was added dropwise hexane solution of n-butyllithium (2.77 M, 24 mL, 65 mmol) at 0 ° C, and then stirred at the same temperature for 30 minutes. A solution of lithium diisopropylamide (LDA) in tetrahydrofuran was prepared. Dissolve methyl butyl oxalate (10 g, 63 mmol) and methyl (benzyloxy)acetate (1 1 g, 59 mmol) in tetrahydrofuran (100 mL) and drop at -78 °C under nitrogen atmosphere After the LD A solution in tetrahydrofuran was prepared, it was stirred at the same temperature for 3 hours. The reaction mixture was warmed to -5 (EtOAc) (EtOAc (EtOAc) (EtOAc) The solvent was evaporated to give the title compound (2-(benzyloxy)-3-oxysuccinic acid 4-tributyl ester 1-methyl ester (23 g).

The obtained 2-(benzyloxy)-3-oxysuccinic acid 4-tert-butyl ester 1-methyl ester (7.6 g) and 2-(4-bromophenyl)ethyliminoamine hydrochloride ( 4.4 g, 16 mmol) was dissolved in MeOH (25 mL). Hydrochloric acid (1 M, 50 mL) was evaporated. lH-NMR (500MHz, DMCO-d6) <5: 13.15 (1H, brs), 7.54 (2H, d, J = 8 Hz), 7.41-7.32 (5H, m), 7.27 (2H, d, J = 8 Hz), -56- 200948788 5.11 (2H,.s), 3.84 (2H, s), 1.41 (9H, s). (4) ({[5-(Benzyloxy)-2-(4-bromobenzyl)-6-hydroxypyrimidin-4-yl]carbonyl}amino) ethyl acetate

Dissolve tert-butyl 5-(benzyloxy)-2-(4-bromobenzyl)-6-hydroxypyrimidine-4.carboxylate (1.0 g, 2.1 mmol) in tetrahydrofuran (5 mL) and methanol (5 The mixed solvent of mL) was added with a sodium hydroxide aqueous solution (8 M, 1.6 mL), and stirred at 50 ° C for 5 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. -Hydroxypyrimidine-4-carboxylic acid as a white solid. This was dissolved in N,N-dimethylformamide (8 mL), and then added, yt-carbonyl-bis(1H-imidazole) (0.57 g, 3.5 mmol), and stirred at room temperature for 1 hour. After the addition of ethyl glycinate (0.66 g, 4.7 mmol) and diisopropylethylamine (1.2 mL, 7.1 mmol), the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj MS m/z : 500 (M + H)+ ; lH-NMR (500MHz, CDC13) (5: 11.84 (1H, s), 8.05 (1H, s), 7.52-7.51 (2H, m), 7.42-7.40 (2H, m), 7.36-7.29 (3H, m), 7.22-7.21 (2H, m), 5.31 (2H, s), 4.25 (2H, q, J = 7 Hz), 4.16 (2H, s), 3.96 (2H, s), 1.31 (3H, t, J = 7 Hz). Reference Example 2 ({[5-(Benzyloxy)-2-(4-hydroxybenzyl)-6-methylpyrimidine-4 ·carbonyl]carbonyl}amino)ethyl acetate-57- 200948788

(1) 5-(benzyloxy)-6-hydroxy-2-(4-hydroxybenzyl)pyrimidine-4-carboxylic acid tert-butyl ester

The title compound (4.8 g, 12 mmol) was obtained as a white solid (yield: 78%). NMR (500MHz, CD30D) <5: 7.44-7.43 (2H, m), 7.36- 7.31 (3H, m), 7.12 (2H, d, J = 9 Hz), 6.74 (2H, d, J = 9 Hz ), 5.17 (2H, s), 3.81 (2H, s), 1.49 (9H, s). (2) T-butyl 2-(4-acetoxybenzyl)-5-(benzyloxy)-6-hydroxypyrimidine-4-carboxylate

第三5-(Benzyloxy)-6-hydroxy-2-(4-hydroxybenzyl)pyrimidine-4-carboxylic acid tert-butyl ester (1.0 g, 2.5 mmol) and pyridine (5 mL) were dissolved in dichloro Methane (5 mL) was added at EtOAc (0.46 mL, 4.9 mmol). After the reaction mixture was diluted with methylene chloride (30 mL). The obtained residue was purified by silica gel column chromatography (Sen Technology Co., Ltd., elution solvent: hexane/ethyl acetate), and was subjected to thin layer chromatography with Rf 値 = 0.70 (hexane/ethyl acetate = 1/1). The title compound (0.97 g, 2.2 mmol. -58- 200948788 lH-NMR (500MHz, CDC13) <5: 7.47-7.46 (2H, m), 7.38-7.32 (3H, m), 7.37 (2H, d, J = 8 Hz), 7.02 (2H, d, J = 8 Hz), 5.24 (2H, s), 3·99 (2H, s), 2.29 (3H, s), 1.53 (9H, s). (3) 2-(4-Ethyloxybenzyl)-5-(benzyloxy)-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidine-4-carboxylic acid tert-butyl ester

2-(4-Ethyloxybenzyl)-5-(benzyloxy)-6-hydroxypyrimidine 4-carboxylic acid tert-butyl ester (Q.97 g, 2.2 mmol) and pyridine (0.53 mL, 6.6 Ethyl acetate was dissolved in dichloromethane (20 mL), and then trifluoromethanesulfonic acid anhydride (0.93 g, 3.3 mmol) was added at 0 ° C. The organic matter was extracted with dichloromethane by adding water to the reaction mixture. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (sssssssssssssssssssssssssssssss The title compound (1.3 g, 2.2 mmol) was obtained as a pale yellow oil (yield of yield). lH-NMR (500MHz, CDC13) (5: 7.42-7.36 (7H, m), 7.03-7.02 (2H, m), 5.11 (2H, s), 4.23 (2H, s), 2.29 (3H, s), 1.56 (9H, (4) 2-(4-Ethyloxybenzyl)-5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid tert-butyl

-59- 200948788 3-(4-Ethyloxybenzyl)-5-(benzyloxy)-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidine-4-carboxylic acid III a solution of butyl ester (1.3 g, 2.2 mmol) in tetrahydrofuran (40 mL) with methylboronic acid (0.26 g, 4.3 mmol), silver oxide (1.3 g, 5.4 mmol), potassium carbonate (0·90 g, 6.5 mmol) Further, [1,1,-bis(diphenylphosphino)ferrocene]palladium dichloride methylene chloride complex (0.26 g, 0.32 mmol) was heated under reflux for 5 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, ethyl acetate was added to filter the insoluble material. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (yield: hexane/ethyl acetate), and Rf 値 = 0.45 (hexane/ethyl acetate = 3) The title compound (0.39 g, 1.1 mmol) was obtained as a pale yellow oil (yield 50%). lH-NMR (400MHz, CDC13) <5: 7.42-7.36 (7H, m), 7.01-6.99 (2H, m), 4.99 (2H, s), 4.23 (2H, s), 2.44 (3H, s) , 2.29 (3H, s), 1.58 (9H, s). (5) ({[5-(Benzyloxy)-2-(4-hydroxybenzyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate ethyl 2-(4-acetamidine) Oxybenzyl)-5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid tert-butyl ester (0.39 g, 1.1 mmol) dissolved in tetrahydrofuran (4.0 mL), methanol (4.0 mL) The aqueous sodium hydroxide solution (8 M, 2.0 mL) was stirred at 50 ° C for 5 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, and the obtained residue was added to hydrochloric acid (1 M, 50 mL) at 0 ° C to precipitate a solid. The solid was filtered off and dried under reduced pressure to give 5-(benzyloxy)-6-methyl-2-(4-hydroxybenzyl)pyrimidine-4-carboxylic acid (0.29 g) as a white solid. 200948788

This was dissolved in tetrahydrofuran (30 mL) and ethanol (5 mL), then added ethyl glycinate (0.14 g, 1.0 mmol) and 4-methylmorpholine (0.11 mL, 1.0 mmol) Stir for 5 minutes. After the reaction solution was added 4-(4,6-dimethoxy-1,3,5-triton-2-yl)-4-methylmorpholinyl chloride (0.28 g, 1.0 mmol), Stir at room temperature for 12 hours. After the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (ssssssssssssssssssssssssssssssss The title compound (0.39 g, 0.83 mmol) was obtained. MS m/z : 436 (M + H) + ; lH-NMR (400MHz, CDC13) <5: 8.33 (1H, t, J = 6 Hz), 7.48- 7.46 (2H, m), 7.39-7.34 ( 3H, m), 7.24 (2H, d, J = 8 Hz), 6.78 (2H, d, J = 8 Hz), 5.31 (2H, s), 4.27 (2H, q, J = 7 Hz), 4.21 ( 2H, d, J = 6 Hz), 4.16 (2H, s), 2.44 (3H, s), 1.32 (3H, t, J = 7 Hz). Reference Example 3 ({[5-(Benzyloxy)-6-methyl-2-(4-{[(trifluoromethyl)sulfonyl)oxy}benzyl)pyrimidin-4-yl]carbonylindole Amino ethyl acetate

Reference Example 2-(3), using ({[5-(benzyloxy)-2-(4-hydroxybenzyl)-6-methylpyrimidin-4-yl)carbonyl}amino)acetate ( The title compound (0.18 g, 0.32 mmol. -61- 200948788 lH-NMR (500MHz, CDC13) <5 : 8.24 (1H, t, J = 5 Hz), 7.47- 7.34 (7H, m), 7.24-7.22 (2H, m), 5.10 (2H, s), 4.27 (2H, q, J =7 Hz), 4.26 (2H, s), 4.20 (2H, d, J = 5 Hz), 2.45 (3H, s), 1.32 (3H,t,J 2 7 Hz). Reference Example 4 ({[5-(Benzyloxy)-2-(4-[(t-butoxycarbonyl)(phenyl)amino]benzyl) 6-methylpyrimidin-4-yl]carbonyl}amine Base) ethyl acetate 0

(1) (4-methylphenyl)phenylaminecarboxylic acid tert-butyl ester

N-(4-tolyl)aniline (1.8 g, 10 mmol), diacetic acid dibutyrate (2.4 g, 11 mmol), triethylamine (2.1 mL, 15 mmol) and N,N- Methylpyridin-4-amine (0.050 g) was dissolved in dichloromethane (50 mL) and acetonitrile (50 mL), and stirred at 5 (TC) for 17.5 hr. The reaction mixture was concentrated under reduced pressure. Purification by chromatography (Biotage, elution solvent: hexane / ethyl acetate), and concentrated under reduced pressure with Rf 値 0.55 (hexane/ethyl acetate = 10/1) of thin layer chromatography. The title compound (0.90 g, 3.2 mmol) (yield: 32%). 1H-NMR (500MHz, CD30D) 5: 7.34-7.11 (7H, m), 7.12 (2H, d, J = 4 Hz), 2.35 ( 3H, s), 1.47 (9H, s). (2) Tri-butyl (-bromomethyl)phenyl]phenylaminecarboxylate-62- 200948788

Br (3-methylphenyl)phenylaminecarboxylic acid tert-butyl ester (3.3 g, 12 mmol), N-bromosuccinimide (2.1 g, 12 mmol) and 2,2'-azobis ( Isobutyronitrile) (0.094 g, 0.58 mmol) was dissolved in carbon tetrachloride (90 mL). The reaction mixture was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (Biotage, elution solvent: hexane/ethyl acetate), and Rf 値 = 0.45 (hexane/ethyl acetate = 10) The title compound (3.5 g, 9.7 mmol) (yield: 84%) was obtained. 1H-NMR (500MHz, CDC13) <5: 7.36-7.17 (9H, m), 4.47 (2H, s), 1.45 (9H, s). (3) [4-(Cyanomethyl)phenyl]phenylaminecarboxylic acid tert-butyl ester

第三[4-(Bromomethyl)phenyl]phenylaminecarboxylic acid tert-butyl ester (3.5 g, 9.7 mmol), acetone cyanohydrogen (1·8 mL, 19 mmol) and 1,8-dioxin Bicyclo[5,4,0]undec-7-ene (2.9 mL, 19 mmol) was dissolved in EtOAc (35 mL). The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (Biotage, elution solvent: hexane/ethyl acetate), and Rf 値 = 0.40 (hexane/ethyl acetate = 4) The title compound (1.2 g, 4.0 mmol) (yield: 41%). -63- 200948788 1H-NMR (500MHz, CDC13) 5 : 7.34-7.18 (9H, m), 3.72 (2H, s), 1.45 (9H, s). (4) [4-(2-Amino-2-imidoethyl)phenyl]phenylaminecarboxylic acid tert-butyl acetate acetate

[4-(Cyanomethyl)phenyl]phenylamine carboxylic acid tert-butyl ester (1.2 g, 4.0 mmol), heated in a solution of aqueous amine (50%, 0.53 g, 8.0 mmol) in ethanol (10 mL) 1.5 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. 15 hours. The reaction mixture was dissolved in EtOAc (EtOAc)EtOAc. After evaporating the solvent under reduced pressure, the obtained white solid was washed with diisopropyl ether (25 mL). This was dissolved in ethanol (40 mL) and dichloromethane (20 mL), and then 10% palladium-activated carbon (0.20 g) was added, and the mixture was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. After the reaction mixture was filtered, EtOAc (EtOAc m. 1H-NMR (400MHz, CD30D) δ: 7.37-7.21 (9Η, m), 3.78 (2H, s), 1.90 (3H, s), 1.43 (9H, s). (5) 5-(Benzyloxy)-2-{4-[(tatabutoxycarbonyl)(phenyl)amino]benzyl hydroxypyrimidine-4-carboxylic acid tert-butyl ester -64- 200948788

C

Reference Example 1-(3), [4-(2-Amino-2-imidoethyl)phenyl]phenylaminecarboxylic acid tert-butyl acetate (1.4 g, 3.5 mmol) (0.69 g, 1.2 mmol) (yield 34%). 1H-NMR (400MHz, CD30D) δ : 10.46 (1Η, s), 7.44-7.18 (14H, m), 5.22 (2H, s), 3.97 (2H, s), 1.52 (9H, s), 1.44 (9H , 〇(6)({[5-(benzyloxy)-2-{4-[(t-butoxycarbonyl)(phenyl)amino]benzyl) 6-methylpyrimidin-4-yl]carbonyl Uanyl)ethyl acetate imitation reference example 2-(3)~reference example 2-(5), using 5-(benzyloxy)-2-(4-[(t-butoxycarbonyl)(phenyl) Amino]benzyl bromide 6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (0·69 g, 1.2 mmol) gave the title compound (0.14 g, 0.22 mmol) (yield 32%) 〇1H-NMR ( 500MHz, CDC13) <5 : 8.31 (1H, t, J = 4 Hz), 7.47 (2H, d, J = 4 Hz), 7.39-7.14 (12H, m), 5.09 (2H, s), 4.25 ( 2H, q, J = 8 Hz), 4.20 (2H, d, J = 4 Hz), 2.44 (3H, s), 1.44 (9H, s), 1.31 (3H, t, J = 8 Hz). Reference example 5 ({[5-(Benzyloxy)-2-(biphenyl-4-ylmethyl)-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl} Amino ethyl acetate

-65- 200948788 (1) 5-(Benzyloxy)-2·(biphenyl-4-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester

Reference Example 4-(4), Reference Example 1-(3), m.p.p. 3%). lH-NMR (500MHz, CDC13) <5: 12.2 (1H, s), 7.53-7.50 (3H, m), 7.48 (3H, d, J = 7 Hz), 7.44-7.40 (4H, m), 7.36 -7.31 ^ (4H, m), 5.25 (2H, s), 4.04 (2H, s), 1.53 (9H, s). (2) ({[5-(Benzyloxy)-2-(biphenyl-4-ylmethyl)-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl] Carbonyl}amino)ethyl acetate

Dissolve 3·(benzyloxy)-2-(biphenyl-4-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (4.5 g) in methanol (45 mL) and tetrahydrofuran (45 The solvent was mixed with MgSO.sub.2, and then aqueous sodium hydroxide (8 M, 15 mL, 120 mmol) was added and stirred at 60 ° C for 3 hours. The reaction solution was cooled to room temperature and then concentrated. After adding hydrochloric acid (1 M, 150 mL) to the obtained residue, ultrasonic treatment was carried out to precipitate a solid. The obtained solid was filtered, dried under reduced pressure to give 5-(benzyloxy)-2-(biphenyl-4-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid (4.5 g, 11 mmol). Yield 73%). 5-(Benzyloxy)-2-(biphenyl-4-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid (4.5-66-200948788 g, 1 1 mmol), 1,1'-carbonyl Bis(1H-impurine) (CDI) (2·1 g, 13 mmol) and diisopropylethylamine (5.8 mL, 33 mmol) dissolved in N,N-dimethylformamide (5 0 After stirring for 1 hour at room temperature, ethyl glycinate (2.3 g, 17 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. ethyl acetate (150 mL). After the organic layer was dried over sodium sulfate, the filtrate was concentrated under reduced pressure. The obtained residue was washed with diisopropyl ether (1 mL) and dried under reduced pressure to give ({[5-(benzyloxy)-2). -(Biphenyl-4-ylmethyl)-6-hydroxypyrimidin-4-mercapto]p-amino}amino)acetic acid ethyl acetate (4.3 g, 8.7 mmol) (yield: 79%). Ethyl ({[5-(benzyloxy)-2-(biphenyl-4-ylmethyl)-6-hydroxypyrimidin-4-yl]carbonyl}amino)acetate (4.3 g, 8.7 mmol) Pyridine (2.1 mL, 26 mmol) was dissolved in dichloromethane (35 mL). EtOAc (EtOAc m. 30 points. The reaction solution was poured into water, extracted with dichloromethane, and the organic layer was dried over sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel chromatography (yield, EtOAc/EtOAc), and Rf 値 = 0.50 (hexane/ethyl acetate) The title compound (4.9 g, 7.8 mmol) (yield: 89%) of the title compound (1H-NMR (400 MHz, CDC13) δ: 8.14 (1 Η, t, J = 8) Hz), 7.59-7.32 (14H, m), 5.22 (2H, s), 4.29 (2H, s), 4.27 (2H, q, J = 8 Hz), 4.22 (2H, d, J = 8 Hz), 1.32 (3H, t, J = 8 Hz). Example 1 ({[2-(3,4-Dichlorobenzyl)-5-hydroxy-6.methylpyrimidin-4-yl]carbonyl}amino)ethyl-67- 200948788

(1) ({[5-(Benzyloxy)-2-(3,4-dichlorobenzyl)-6-indole[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl] Carbonyl}amino)ethyl acetate

Reference Example 4-(4), Reference Example 1-(3), Reference Example 5-(2), (3,4-dichlorophenyl)acetonitrile (9.3 g, 50 mmol) g, 6.9 mmol) white solid (yield 34%). 1H-NMR (500MHz, CDC13) δ : 8.05 (1H, t, J = 8 Ηζ), 7.49-7.34 (7Η, m), 7.19 (1Η, d, J = 8 Hz), 5.23 (2H, s), 4.28 (2H, q, J = 8 Hz), 4.22 (2H, d, J = 8 Hz), 4.19 (2H, s), 1.33 (3H, t, J = 8 Hz). (2) ({[5-(Benzyloxy)-2-(3,4-dichlorobenzyl)-6-methylpyrimidin-4-yl]carbonyl}amino) ethyl acetate

Referring to Example 2-(4), ({[5-(benzyloxy)-2-(3,4-dichlorobenzyl)-6-{[(trifluoromethyl)sulfonyl]oxy) Ethyl pyrimidine-4-yl]carbonyl}amino)acetate (0.62 g, 1.0 mmol) 1H-NMR (400MHz, CDC13) (5: 8.25 (1H, t, J = 8 Hz), -68- 200948788 7.47-7.34 (7H, m), 7.21 (1H, d, J = 8 Hz), 5.10 ( 2H, s), 4.27 (2H, q, J = 8 Hz), 4.22 (2H, d, J = 4 Hz), 4.18 (2H, s), 2.44 (3H, s), 1 _32 (3H, t, J = 8 Hz) (3) ({[2-(3,4-Dichlorobenzyl)-5-hydroxy-6-methyl spurred _4_yl] benzyl) amino) ethyl acetate

Ethyl ({[5-(benzyloxy)-2-(3,p-dichlorobenzyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.23 g, 0.48 mmol) After adding 5% palladium-activated carbon (150 mg) to ethyl acetate (30 mL), the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (Sen Technology Co., Ltd., elution solvent: hexane/ethyl acetate), and Rf 値 = 0.60 (hexane/ethyl acetate = 4/1) corresponding to thin layer chromatography. The title compound (0.14 g, 0.36 mmol). 1H-NMR (400MHz, CDC13)5: 11.42 (1H, s), 8.38 (1H, t, J = 8 Hz), 7.41 (1H, s), 7.36 (1H, d, J = 8 Hz), 7.17 ( 1H, d, J = 8 Hz), 4.28 (2H, q, J = 8 Hz), 4.20 (2H, d, J = 8 Hz), 4.12 (2H, s), 2.52 (3H, s), 1· 33 (3H, t, J = 8 Hz). (4)({ [2-(3,4-Dichlorobenzyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid ({[2-(3,4-) Ethyl dichlorobenzyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonylguanidino)acetate (0.14 g, 0.36 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL) The solvent was stirred at 40 ° C for 1 hour with an aqueous sodium hydroxide solution (1 M, 5.0 mL). After the reaction mixture was concentrated under reduced pressure, hydrochloric acid (1 M) was added, and the mixture was subjected to ultrasonic treatment to precipitate a solid. The resulting solid was filtered, dried <jjjjjjjjjjj Mp 17 2- 174 °C ;

1H-NMR (500MHz, CD30D) (5: 7.50 (s, 1H), 7.41 (1H, d, J = 8 Hz), 7.26 (2H, d, J = 8 Hz), 4.15 (2H, s), 4.14 (2H, s), 2.48 (3H, s).

Example 2 [({5-Hydroxy-6-methyl-2-[(4-trifluoromethyl)benzyl]pyrimidin-4-yl}carbonyl)amino]acetic acid] cold 丫(1)( {[ 5-(Benzyloxy)-2-[(4-trifluoromethyl)benzyl]-6-U(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino) Ethyl acetate

Reference Example 4-(4), Reference Example 5-(2), m.p. (4-(trifluoromethyl)phenyl]acetonitrile (3.7 g, 20 mmol) Solid (yield 30%). 1H-NMR (400MHz, CDC13) 5 : 8.06 (1H, t, J = 8 Hz), 7.59 (2H, d, J = 12 Hz), 7.49-7.34 (5H, m), 7.34 (2H, d, J = 12 Hz), 5.22 (2H, s), 4.31 (2H, s), 4.28 (2H, q, J = 8 Hz), 4.21 -70- 200948788 (2H,d,J = 8 Hz), 1.33 (3H , t, J = 8 Hz). (2) [({5-(Benzyloxy)-6-methyl·2-[(4-trifluoromethyl)benzyl]pyrimidin-4-yl}carbonyl)amino]acetate

Reference Example 2-(4), using ({[5-(benzyloxy)-2-[(4-trifluoromethyl)benzyl]-6-{[(trifluoromethyl)sulfonyl] Ethyloxy}pyrimidin-4-yl]carbonyl-U-ethyl)acetate (0-62 g, 1 EtOAc) 1H-NMR (400MHz, CDC13) 5 : 8.26 (1H, t, J = 4 Hz), 7.57 (2H, d, J = 12 Hz), 7.49-7.46 (3H, m), 7.40-7.32 (4H, d , J = 12 Hz), 5.09 (2H, s), 4.29 (2H, s), 4.26 (2H, q, J = 8 Hz), 4.20 (2H, d, J = 4 Hz), 4.18 (2H, s ), 2.45 (3H, s), 1.31 (3H, t, J = 8 Hz). (3) [({5-Hydroxy-6-methyl-2-[(4-trifluoromethyl)benzyl]pyrimidin-4-yl}carbonyl)amino]]acetic acid imitation Example 1-(3 , using [({5-(benzyloxy)-6-methyl-2-(4-trifluoromethyl)benzyl]pyrimidin-4-ylindole carbonyl)amino]acetate (0.23 g, The title compound (0.14 g, 0.35 mmol) (yield: 73%). 1H-NMR (400MHz, CDC13) &lt;5: 11.40 (1H, s), 8.39 (1H, t, J = 8 Hz), 7.55 (2H, d, J = 8 Hz), 7.44 (2H, d, J = 8 Hz), 4.28 (2H, q, J = 8 Hz), 4.23 (2H, s), 4.19 (2H, d, J = 8 Hz), -71- 200948788 2.52 (3H, s), 1.32 (3H , t, J = 8 Hz). (4) [({5-Hydroxy-6-methyl-2-[(4-trifluoromethyl)benzyl]pyrimidin-4-ylindolecarbonyl)amino]acetic acid imitation Example 1-(4), Using [({5-hydroxy-6-methyl-2-[(4-trifluoromethyl)benzyl]pyrimidin-4-yl}carbonyl)amino]acetate (0.14 g, 0.35 mmol) The title compound (0.13 g, 0.31 mmol. Mp 1 5 8- 1 59 t ; 1H-NMR (400MHz, CD30D) δ : 7.57 (2Η, d, J = 8 Hz), 7.51 (2H, d, J = 8 Hz), 4.27 (2H, s), 4.14 (2H, s), 2.48 (3H, s). Example 3 ({[5-Hydroxy-6-methyl-2-(2-naphthylmethyl)pyrimidin-4-yl)carbonyl}amino)acetic acid (1) ({[5-(benzyloxy)-) Ethyl 2-(2-naphthylmethyl)-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate

The title compound (5.1 g, 8.4 mmol) (yield: 28%) 1H-NMR (500MHz, CDC13) &lt;5: 8.12 (1H, t, J = 4 Hz), 7.82-7.80 (4H, m), 7.50-7.43 (5H, m), 7.38-7.31 (3H, m) , 200948788 J = 8 Hz), 4.20 (2H, 5.20 (2H, s), 4.41 (2H, s), 4.26 (2H, d, J = 4 H z), 1.3 1 (3 H, t, J = 8 H z) · (2) ({[5-(decyloxy)-6-methyl-2-(2-naphthylmethyl) mouth spray _4 base] ethyl acetamide) ethyl acetate

Referring to Example 2-(4), using ({[5-(hydroxy)-2-(2-naphthylmethyl)-6-{[(trifluoromethyl))]oxy) 3⁄4 steep The title compound (0.23 g, 0.48 mmol) (yield: 48%). 1H-NMR (500MHz, CDC13) 5 : 8.34 (1H, t, J = 4 Hz), 7.82-7.79 (4H, m), 7.50-7.33 (BH, m), 5.08 (2H, s), 4.41 (2H , s), 4.25 (2H, q, J = 8 Hz), 4.20 (2H, d, J = 4 Hz), 2.45 (3H, s), 1.30 (3H, t, J = 8 Hz). (3) ({[5-Hydroxy-6-methyl-2-(2-naphthylmethyl)pyrimidin-4-yl)carbonyl}amino)acetate ◎ coni^0p〇0&quot; (3), ethyl ({[5-(benzyloxy)-6-methyl-2-(2-naphthalenyl)pyrimidin-4-yl)carbonyl}amino)acetate (0.23 g, 0.48 mmol The title compound (0.16 g, 0.42 mmol) (yield: 88%). 1H-NMR (500MHz, CDC13) 5 : 11.38 (1H, s), 8.44 (1H, t, J = 8 Hz), 7.80-7.75 (4H, m), 7.49-7.40 (3H, m), 4.35 (2H , s), 4.26 (2H, q, J = 8 Hz), 4.18 (2H, d, J = 8 Hz), 2.52 (3H, s), 1.31 (3H, t, J = 8 Hz). -73- 200948788 (4) ({[5-Hydroxymethyl-2-(2-naphthylmethyl)pyrimidin-4-yl)carbonyl}amino)acetic acid imitation Example 1-(4), using ({[ Ethyl 5-hydroxy-6-methyl-2-(2-naphthalenyl)pyrimidin-4-yl]carbonyl}amino)acetate (0.16 g, 0.42 mmol) ) White solid (yield 93%). Mp 119-120 °C ; 1H-NMR (400MHz, CD30D) δ : 7.79-7.73 (4Η, m), 7.49-

7.38 (3H,m), 4.34 (2H,s), 4.14 (2H,s), 2.48 (3H,s). Example 4 ({[2-(biphenyl-4-ylmethyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino) hydrazine acetate (1) ({[5-(benzyl) Ethyloxy-2-(biphenyl-4-ylmethyl)-6-methylpyrimidin-4-yl]carbonyl}amino)ethyl acetate

Imitative Reference Example 2-(4), obtained with Reference Example 5-(2) ({[5-(Benzyloxy)-2-(biphenyl-4-ylmethyl)-6-{[(trifluoro) Methyl)sulfonyl]oxypyrimidin-4-yl]carbonyl}amino)acetic acid (0.63 g, 1.0 mmol) 1H-NMR (500MHz, CDC13) &lt;5: 8.35 (1H, t, J = 8 Hz), 7.59-7.54 (2H, m), 7.49-7.31 (12H, m), 5.09 (2H, s), 4.29 -74- 200948788 (2H, s), 4.26 (2H, q, J = 8 Hz), 4.22 (2H, d, J = 8 Hz), 2.46 (3H, s), 1 _3 1 (3H, t, J = 8 Hz). (2) ({ [2-(biphenyl-4-ylmethyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amine) ethyl acetate

〇

Example 1-(3), using ({[5-(benzyloxy)-2-(biphenyl-4-ylmethyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid Ethyl ester (0.27 g, 0.55 mmol). 1H-NMR (500MHz, CDC13) 5 : 11.37 (1H, s), 8.45 (1H, m), 7.58-7.52 (4H, m), 7.44-7.40 (3H, m), 7.35-7.30 (2H, m) , 4.26 (2H, q, J = 8 Hz), 4.23 (2H, s), 4.19 (2H, d, J = 8 Hz), 2·53 (3H, s), 1.32 (3H, t, J = 8 Hz). (3) ({[2-(Biphenyl-4-ylmethyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid imitation Example 1-(4), used ( Ethyl acetate (0.19 g, 0.47 mmol) g, 0.48 mmol) white solid (quantitative yield). Mp 201-202 ° C ; Calculated enthalpy analysis C21H19N304 : C, 66.8 3; H, 5.07 ; N, 11.13. Measured 値C, 66.79; H, 5.28; N, 11.06; 1H-NMR (400MHz, CD30D) 5 : 7.58 -7.52 (4H, m), 7.41- 7.38 (4H, m), 7.30-7.28 (1H, m), 4.22 (2H, s), 4.15 (2H, s), 2_49 (3H, s). -75- 200948788 Example 5 ({[2-(biphenyl-4-ylmethyl)-6-ethyl-5-hydroxypyran-4-yl]carbyl}amino)acetic acid

(1) ({[5-(Hydroxy)-2-(biphenyl-4-ylmethyl)·6-ethyl-pyridylpyran-4-yl]] hydrazino}amino)ethyl acetate

((5-(Benzyloxy)-2-(biphenyl-4-ylmethyl)-6-{[(trifluoromethyl)sulfonyl]oxy})). Pyrimidin-4-yl]carbonyl)amino)acetate (0.32 g, 0.50 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborane (0.093 mL, 0_55 mmol), sodium carbonate (0.16 g, 1.5 mmol) and hydrazine (triphenylphosphine) palladium (0.035 g, 0.050 mmol) dissolved in 1,2-dimethoxyethane (2 mL) and water (0.51 mL), heated under reflux for 2 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, it was extracted with ethyl acetate, and the extract was dried over sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (yield solvent: hexane/ethyl acetate), and Rf 値. The title compound (0.11 g, 0.21 mmol) (yield: 41%). 1H-NMR (500MHz, DC13) δ : 8.31 (1Η, t, J = 4 Hz), 7.60- 7.31 (14H, m), 7.13 (1H, dd, J = 8 Hz, 4 Hz), 6.70 (1H, Dd, J = 8 Hz, 4 Hz), 5.66 (1H, dd, J = 8 Hz, 4 Hz), 5.07 (2H, s), -76- 200948788 4.33 (2H, s), 4.26 (2H, q, J = 8 Hz), 4.21 (2H, d, J = 4 Hz), 1_31 (3H, t, J = 8 Hz). (2) ({[2-(Biphenyl-4-ylmethyl)-6-ethyl-5-hydroxypyrimidin-4)yl]-yl}amino)ethyl acetate

Example 1-(3), using ({[5-(benzyloxy)-2-(biphenyl-4-ylmethyl)-6-vinylpyrimidin-4-yl]carbonyl}amino)acetic acid Ethyl ester (0.11 2 〇·············································· 46 (1H, t, J = 8 Hz), 7.58-7.52 (4H, m), 7.44-7.40 (3H, m), 7.34- 7.31 (2H, m), 4.27 (2H, q, J = 8 Hz) , 4.24 (2H, s), 4.19 (2H, d, J = 8 Hz), 2.90 (2H, q, J = 8 Hz), 1.31 (6H, t, J = 8 Hz)

(3) U [2-(biphenyl-4-ylmethyl)-6-ethyl-5-hydroxypyrimidin-4-yl]carbonyl Uan)acetic acid imitation Example 1-(4), using ({ Ethyl [2-(biphenyl-4-ylmethyl)-6-ethyl-5-hydroxypyrimidin-4-yl]carbonyl}amino)acetate (0.064 g, 0.15 mmol) , 0.14 mmol) white solid (yield: 93%). Mp 1 75-176 t:; 1H-NMR (500MHz, CD30D) (5: 7.58-7.52 (4H, m), 7.41- 7.38 (4H, m), 7.30-7.28 (1H, m), 4.23 (2H, s), 4.14 (2H, s), 2.88 (2H, q, J = 8 Hz), 1.28 (3H, t, J = 8 Hz). Example 6 -77- 200948788 [({2-[(4') -chlorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

(1) [({5-(Benzyloxy)-2-[(4'-chlorobiphenyl-4-yl)methyl]-6-hydroxypyrimidin-4-yl}carbonyl)amino]ethyl acetate

O. ({[5-(Benzyloxy)-2-(4-bromobenzyl)-6-hydroxypyrimidin-4-yl]carbonyl}amino) ethyl acetate obtained in Reference Example 1-(4) (500 mg, 1.0 mmol), (4-chlorophenyl)boronic acid (310 mg, 2.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium chloride dichloride (82 mg, 0.010 mol) and tripotassium phosphate 3 hydrate (640 mg, 3.0 mmol) were dissolved in 1,2-dimethoxyethane (30 mL). After the reaction solution was cooled to room temperature, water was poured and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. EtOAc m. ). MS m/z : 532 (M + H) + ; lH-NMR (400MHz, CDC13) 5 : 8.15 (1H, d, J = 8 Hz), 8.11 (1H, t, J = 5 Hz), 7.74 (1H , d, J = 8 Hz), 7.53-7.31 (11H, m), 5.36 (2H, s), 4.26 (2H, q, J = 7 Hz), 4.17 (2H, d, J = 5 Hz), 4.06 (2H, s), 1.31 (3H, t, J = 7 Hz). -78- 200948788 (2) [({5-(Benzyloxy)-2-[(4'-chlorobiphenyl-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amine Ethyl acetate

Reference Example 2-(3), Reference Example 2-(4), using [({5-(benzyloxy)-2-[(4'-chlorobiphenyl-4-yl)methyl]-6-) Ethyl acetate (60 mg, 0.11 mmol lH-NMR (400MHz, CDC13) 5 : 8.34 (1H, t, J = 5 Hz), 7.52- 7.43 (8H, m), 7.39-7.32 (5H, m), 5.09 (2H, s), 4.28 (2H , s), 4.26 (2H, q, J = 7 Hz), 4.22 (2H, d, J = 5 Hz), 2.46 (3H, s), 1.3 1 (3H, t, J = 7 Hz). (3) [({2-[(4'-chlorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

o Example 1-(3), using [({5-(benzyloxy)-2-[(4'-chlorobiphenyl-4-yl)methyl]-6-methylpyrimidin-4-yl) Ethyl acetate (30 mg, 0.057 mmol) EtOAc (mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj s), 8.45 (1H, t, J = 6 Hz), 7.50 (2H,d, ;f 2 8 Hz), 7.49 (2H,d, J = 8 Hz), 7.41 (2H, d, J = 8 Hz) ), 7.38 (2H, d, J = 8 Hz), 4.28 (2H, q, -79- 200948788 J = 7 Hz), 4.22 (2H, s), 4.20 (2H, d, J = 6 Hz), 2.53 (3H, s), 1.32 (3H, t, J = 7 Hz). (4) [({2-[(4-Chlorobiphenyl-4-yl)methyl]-5-carbyl-6-methylpyran-4-yl}carbonyl)amino]acetic acid imitation Example 1 -(4), using [({2-[(4'-chlorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate The title compound (17 mg, 0.041 mmol. Mp 213 °C; MS m/z: 412 (M + H) + ; 1H-NMR (400MHz, CDC13) (5: 11.30 (1H, s), 8.42 (1H, t, J 2 5 Hz), 7.48 ( 4H,d,J = 8 Hz), 7.38 (4H, dd, J = 10 Hz, 8 Hz), 4.28 (2H, d, J = 6 Hz), 4.23 (2H, s), 2.54 (3H, s) Example 7 [({2-[(2'-Chlorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

❹ (1)[({5-(Hydroxy)-2-[(2'-chlorobiphenyl-4-yl)methyl]_6-pyridinyl-4-yl}carbonyl)amino]acetic acid Ethyl ester

Example 6-(1), obtained with Reference Example 1-(3) (丨[5_(benzyloxy)-2-(4-bromo)]-6-hydroxypyran-4-yl]carbonyl} Ethyl acetate (5 mg, 1 〇-80-200948788 mmol) and (2-chlorophenyl)boronic acid (310 mg, 2.0 mmol) Yield 34%) » MS m/z: 532 (M + H) + ; lH-NMR (400MHz, CDC13) 5 : 8.07 (1H, t, J = 6 Hz), 7.54 (2H, d, J = 8 Hz), 7.48-7.42 (4H, m), 7.39-7.29 (7H, m), 5.36 (2H, s), 4.26 (2H, q, J = 7 Hz), 4.17 (2H, d, J = 6 Hz ), 4.07 (2H, s), 1.31 (3H, t, J = 7 Hz). (2) [({5-(Benzyloxy)-2-[(2'-chlorobiphenyl-4-yl)methyl]-6-methylpyrimidine-4-

Ethyl}carbonyl)amino]ethyl acetate

Reference Example 2-(3), Reference Example 2-(4), using [({5-(benzyloxy)-2-[(2'-chlorobiphenyl-4-yl)methyl]-6-) Ethylacetate (180 mg, 0.34 mmol 〇lH-NMR (400MHz, CDC13) 5 : 8.35 (1H, t, J = 5 Hz), 7.49- 7.25 (13H, m), 5.11 (2H, s), 4.30 (2H, s), 4.26 (2H, q, J = 7 Hz), 4.22 (2H, d, J = 5 Hz), 2.47 (3H, s), 1.31 (3H, t, J = 7 Hz). (3) [({2-[(2'-chlorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid imitation Example 1- (3), Example 1-(4), using [({5-(benzyloxy)-2-[(2'-chlorobiphenyl-4-yl)methyl]-6-methylpyrimidine-4 -Methyl}carbonyl)amino]ethyl acetate-81 - 200948788 (110 mg, 0.21 mmol) Mp 8 8 〇C ; MS m/z : 412 (M + H) + ; 1H-NMR (400MHz, CDC13) &lt;5: 11.33 (1H, s), 8.43 (1H, t, J = 6 Hz), 7.44 (1H, d, J = 7 Hz), 7.37 (4H, s), 7.31-7.23 (3H, m), 4.26 (2H,d, J = 6 Hz), 4·25 (2H, s), 2.55 (3H, s). Example 8 [({2-[(2-Chlorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)β-amino]acetic acid

(1) 2-Chloro-4-methylbiphenyl

Dissolve 1-bromo-2-chloro-4-methylbenzene (3.6 g, 17 mmol) in tetrahydrofuran (50 mL), and dilute n-butyllithium in hexane at -7 8 °C (1.57 M, 12 mL) After 〇19 mmol), it was stirred at the same temperature for 1.5 hours. Trimethylamine borate (5.4 g) was added to the reaction mixture, and the mixture was warmed to room temperature over 15 hours, and then hydrochloric acid (10%) was added to ethyl acetate. The extract was washed with water and an aqueous solution of sodium chloride before and after the extract, and the organic layer was concentrated under reduced pressure. The obtained residue was dissolved in toluene (100 mL) and water (10 mL), and then iodinated benzene (3.8 g, 19 mmol), hydrazine (triphenylphosphine) palladium (1 g) and sodium carbonate (3.6 g), and then heated to reflux. 3 hours. After the reaction solution was cooled to room temperature, an aqueous ammonium chloride solution was poured and extracted with ethyl acetate. The extract was washed with aqueous sodium chloride -82 - 200948788. After evaporating the solvent under reduced pressure, the residue obtained was purified by silica gel column chromatography (yield: hexane/ethyl acetate), and fractionated by Rf 値 = 0.50 (hexane) of thin layer chromatography. The organic layer was obtained (yield:yield: lH-NMR (500MHz, CDC13) (5: 7.43-7.35 (4H, m), 7.29 (1H, s), 7.24 (1H, d, J = 5 Hz), 7.12 (2H, d, J = 8 Hz) , 2.37 (3H, s) o

(2) 5-(Benzyloxy)-2-[(2-chlorobiphenyl-4-yl)methyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester

Reference Example 4-(2)~4-(4), Reference Example 1-(3), 2-chloro-4-methylbiphenyl (3-0 g, 15 mmol) 3.3 mmol) white solid (yield 23%). lH-NMR (500MHz, CDC13) &lt;5: 7.50-7.30 (13H, m), 5.28

(2H, s), 4.02 (2H, s), 1.53 (9H, s). (3) [({5-(Benzyloxy)-2-[(2-chlorobiphenyl-4-yl)methyl) Ethyl acetate-6-hydroxypyrimidin-4-yl}carbonyl)amino]

Reference Example 1-(4), using 3-(benzyloxy)-2-[(2-chlorobiphenyl-4-yl)methyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester ( The title compound (1.4 g, 2.7 mmol. -83- 200948788 MS m/z : 5 32 (M + H)+ ; lH-NMR (500MHz, CDC13) 5 : 8.06 (1H, t, J = 5 Hz), 7.54 (2H, d, J = 7 Hz ), 7.46-7.37 (6H, m), 7.37 -7.29 (5H, m), 5.37 (2H, s), 4.26 (2H, q, J = 7 Hz), 4.16 (2H, d, J = 5 Hz) , 4.02 (2H, s), 1.31 (3H, t, J = 7 Hz). (4) [({5-(Benzyloxy)-2-[(2-chlorobiphenyl-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetate

Reference Example 2-(3), Reference Example 2-(4), using [({5-(benzyloxy)-2-[(2-chlorobiphenyl-4-yl)methyl]-6-hydroxyl) Ethylpyrimidin-4-ylindole carbonyl)amino]acetate (1.4 g, 2.7 mmol). lH-NMR (500MHz, CDC13) &lt;5: 8.32 (1H, t, J = 5 Hz), 7.48- 7.42 (6H, m), 7.40-7.29 (7H, m), 5.11 (2H, s), 4.28 -4.21 (6H,m), 2.47 (3H, s), 1.31 (3H, t, J = 7 Hz). (5) [({2-[(2-Chlorobiphenyl-4-yl)methyl]-5.hydroxy-6-methylpyrimidin-4-yl)carbonyl)amino]ethyl acetate

Example 1-(3), using [({5-(benzyloxy)-2-[(2-chlorobiphenyl-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl) Ethyl acetate ethyl ester (0.46 g, EtOAc, EtOAc)

lH-NMR (500MHz, CDC13) 5 : 11.43 (1H, s), 8.45 (1H, t, J = 6 Hz), 7.44-7.40 (5H, m), 7.38-7.36 (1H, m), 7.28 (2H , s), 4.29 (2H, q, J 2 7 Hz), 4.21 (2H, d, J = 6 Hz), 4.20 (2H, s), 2.54 (3H, s), 1.32 (3H, t, J = 7 Hz). (6) [({ 2-[(2-Chlorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-ylindolecarbonyl)amino]acetic acid

Example 1-(4), using [({2-[(2-chlorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino] Ethyl acetate (0.28 g, 0.65 mmol) Mp 84-86 °C; MS m/z: 412 (M + H) + ; lH-NMR (500MHz, DMSO-d6) 5 : 12.88 (1H, s), 11.98 (1H, s), 9.49 (1H, t, J = 6 Hz), 7.52 (1H, s), 7.45 (2H, t, J 2 7

Hz), 7.41-7.39 (3H, m), 7.34 (2H, t, J = 8 Hz), 4.20 (2H, s), 4.02 (2H, d, J = 6 Hz), 2.44 (3H, s). Example 9 [({2-[(4*•Fluorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

(1) ({[5-(Benzyloxy)-2-[(4'-fluorobiphenyl-4-yl)methyl]-6-{[(trifluoromethyl)sulfonyl]oxyindole) Pyrimidin-4-yl]carbonyl}amino)ethyl acetate-85- 200948788

OEt

F. Example 6-(1), Reference Example 2_(3), obtained by reference Example i(4) ({[5_(oxy)-2-(4-bromo)]-6-hydroxypyrimidin-4-yl] Carbonyl}amino)acetic acid ethyl acetate (0.50 g, 1.0 mmol) and (4-fluorophenyl)boronic acid (m.p. Substance (yield 57%). lH-NMR (500MHz, CDC13) 5 : 8.12 (1H, t, J = 5 Hz), 7.55-

7.47 (6H, m), 7.42 (2H, d, J= 8 Hz), 7.39-7.35 (3H, m), 7.11 (2H, t, J = 9 Hz), 5.22 (2H, s), 4.28 (2H , s), 4.28 (2H, q, J = 7 H z), 4 · 2 2 (2 H, d, J =: 5 H z), 1.3 2 (3 H, t, J = 7 H z). (2) [({5-(Benzyloxy)-2-[(4'-fluorobiphenyl-4-yl)methyl]-6-methylpyrimidin-4-ylindolecarbonyl)amino]acetic acid B ester

Refer to Example 2-(4) for {[5-(Benzyloxy)-2-[(4'-fluorobiphenyl-4)yl)

Ethyl acetate-6-[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.38 g, 0.57 mmol) Methyl) oily material (yield 89%). lH-NMR (500MHz, CDC13) 5 : 8.34 (1H, t, J = 5 Hz), 7.55- 7.47 (6H, m), 7.44 (2H, d, J = 8 Hz), 7.39-7.33 (3H, m ), 7.11 (2H, t, J = 9 Hz), 5.09 (2H, s), 4.28 (2H, s), 4.26 (2H, q, J =7 Hz), 4.22 (2H, d, J = 5 Hz) ), 2.46 (3H, s), 1.31 (3H, t, J = 7 Hz). (3) [({ 2-[(4'-fluorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}-86- 200948788 carbonyl)amino]acetate B ester

Example 1-(3), using [({5-(benzyloxy)-2-[(4'-fluorobiphenyl-4-yl))

Methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.26 g, 0.51 mmol). lH-NMR (500MHz, CDC13) 5 : 11.38 (3H, s), 8.45 (1H, t, J

=6 Hz), 7.52 (2H, dd, J = 9 Hz, 5 Hz), 7.48 (2H, d, J= 8 Hz), 7.40 (2H, d, J= 8 Hz), 7.10 (2H, t, J = 9 Hz), 4.28 (2H, q, J = 7 Hz), 4.22 (2H, s), 4.20 (2H, d, J = 6 Hz), 2.53 (3H, s), 1.32 (3H, t, J = 7 Hz). (4) [({2-[(4'-Fluorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid imitation Example 1- (4), using [({2-[(4'-fluorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetate ( The title compound (0.17 g, 0.42 mmol) Mp 1 9 6 ° C ; MS m/z ·· 396 (M + H) + ; Calculated 値 analysis C21H18FN304: c, 63.79; H, 4.59; N, 10.63; F, 4.81. Measured 値: c, 63.71 ; , 4.40 ; N, 10.83 ; F, 4.97 ; 1H-NMR (500MHz, CDC13) &lt;5 : 11, .30 (1H, s), 8.43 (1H, t, J = 6 Hz), 7.52-7.46 (4H , m), 7.39 (2H, d, J = 8 Hz), 7.09 -87- 200948788 (2H, t, J = 9 Hz), 4.28 (2H, d, J = 6 Hz), 4.23 (2H, s) , 2.54 (3H, s). Example 10 ({[2-(biphenyl-3-ylmethyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonylguanidino)acetic acid

(1) 5-(Benzyloxy)-2-(biphenyl-3-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester

The title compound (5.1 g, 11 mmol) (yield: 66%). 1H-NMR (500MHz, CDC13) &lt;5: 7.57-7.52 (4H, m), 7.43- 7.27 (10H, m), 5.22 (2H, s), 4.08 (2H, s), 1.52 (9H, s) . (2) ({[5-(Benzyloxy)-2-(biphenyl-3-ylmethyl)-6-hydroxypyrimidin-4-yl]carbonyl}amino)ethyl acetate

Reference Example 1-(4), using 3-(benzyloxy)-2-(biphenyl-3-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (5.1 g, 11 mmol The title compound (4.1 g, 8.3 mmol) (yield: 76%). 1H-NMR (400MHz, CDC13) δ : 8.06 (1Η, m), 7.58-7.29 200948788 (14H, m), 5.34 (2H, s), 4.26 (2H, q, J = 8 Hz), 4.18 (2H, d, J = 4 Hz), 4.10 (2H, s), 1.32 (3H, t, J = 8 Hz). (3) ({[5-(Benzyloxy)-2-(biphenyl-3-ylmethyl)-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidin-4-yl] Carbonyl}amino)ethyl acetate

Referring to Example 2-(3), using ({[5-(benzyloxy)-2-(biphenyl-3-ylmethyl)-6· fluorenylpyrimidin-4-yl]] Ethyl acetate (4.1 g, 8.3 mmol) gave 1H-NMR (500MHz, CDC13) (5: 8.11 (1H, t, J = 4 Hz), 7.59-7.57 (3H, m), 7.50-7.40 (6H, m), 7.39-7.33 (5H, m), 5.22 (2H, s), 4.31 (2H, s), 4.26 (2H, q, J = 8 Hz), 4.20 (2H, d, J = 4 Hz), 1·31 (3H, t, J = 8 Hz (4) ({[5-(Benzyloxy)-2-(biphenyl-3-ylmethyl)-6-methylpyrimidin-4-yl]carbonyl}amino)ethyl acetate

Reference Example 2-(4), using (([5-(benzyloxy)-2-(biphenyl-3-ylmethyl)-6-{[(trifluoromethyl)sulfonyl)oxy) Ethyl pyrimidine-4-yl]carbonyl}amino)acetate (0.63 g, EtOAc) (m. 5 : 8.33 (1H, m), 7.60-7.32 (14H, m), 5.09 (2H, s), 4.31 (2H, s), 4.25 (2H, q, J = 8 Hz), -89- 200948788 4.20 ( 2H, d, J = 4 Hz), 2.45 (3H, s), 1.30 (3H, t, J = 8 Hz) o (5) ({[2-(biphenyl-3-ylmethyl)-5-) Ethyl 6-methylpyrimidin-4-yl]carbonyl}amino)acetate i. Methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.40 g, 0.81 mmol). (500MHz, CDC13) 5 : 11.38 (1H, s), 8.45 (1H, m), 7.59-7.57 (3H, m), 7.47-7.31 (6H, m), 4.26 (2H, q, J = 8 Hz) , 4.25 (2H, s), 4.19 (2H, d, J = 4 Hz), 2.53 (3H, s), 1.31 (3H, t, J = 8 Hz) (6) ({[2-(biphenyl) -3-ylmethyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid Example 1-(4) using ethyl ({[2-(biphenyl-3-ylmethyl)-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl}amino)acetate (0.30 g , </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; ), 7.46- 7.25 (6H, m), 4.25 (2H, s), 4.14 (2H, s), 2_49 (3H, s). Example 1 1 ({[2-(biphenyl-4-ylmethyl) )-6-cyclopropyl-5-hydroxypyrimidin-4-yl]carbonylguanidino)acetic acid-90- 200948788 ο

(1) ({[5-(Benzyloxy)-2-(biphenyl-4-ylmethyl)-6-cyclopropylpyrimidin-4yl]carbonyl}amino)ethyl acetate

〇

Reference Example 2-(4), obtained with Reference Example 5-(2) ({[5-(Benzyloxy)-2-(biphenyl-4-ylmethyl)-6-{[(trifluoromethyl) Ethyl sulfonyl 'oxy}pyrimidin-4-yl]carbonyl}amino)acetic acid ethyl ester (0.63 g, 1.0 mmol) , 0.78 mmol) (yield 78%). 1H-NMR (500MHz, CDC13) (5: 8.33 (1H, t, J = 4 Hz), 7.59-7.49 (6H, m), 7.44-7.31 (8H, m), 5.13 (2H, s), 4.25 ( 2H, q, J = 8 Hz), 4.22 (2H, d, J = 4 Hz), 4.20 (2H, s), 2.47 (1H, m), 1.31 (3H, t, J = 8 Hz), 1.16- 1.12 (2H, m), 1.03-0.99 (2H, m) (2) ({[2-(biphenyl-4-ylmethyl)-6-cyclopropyl-5-hydroxypyrimidin-4-yl] Carbonyl} Amino) Ethyl Acetate 0

Example 1-(3), using ({ [5-(benzyloxy)-2-(biphenyl-4-ylmethyl)-6-cyclopropylpyrimidin-4-yl]carbonyl}amino) The title compound (0.44 g, 0.99 mmol) (yield: 94%) (1H-NMR (500MHz, CDC13) (5: 11.46 (1H, s), 8.47 (1H, m), -91- 200948788 7.58-7.57 (2H, m), 7.52-7.51 (2H, m), 7.43-7.38 (4H, m), 7.34-7.31 (1H, m), 4.27 (2H, q, J = 8 Hz), 4.19 (2H, d, J = 8 Hz), 4.13 (2H, s), 2.54 (1H, m), 1.32 (3H, t, J = 8 Hz), 1.22-1.20 (2H, m ), 1.12-1.10 (2H, m) (3) ({[2-(biphenyl-4-ylmethyl)-6-cyclopropyl-5-hydroxypyrimidin-4-yl]carbonyl} Amino) Acetic acid imitation Example 1-(4), using (丨[2-(biphenyl-4-ylmethyl)-6-cyclopropyl-5-hydroxypyrimidin-4-yl]carbonyl}amino)acetate (0.44 g, 0.99 mmol) ield: Compound Compound Compound Compound Compound Compound Compound Compound (2H, m), 7.53- 7.50 (2H, m), 7.41-7.35 (4H, m), 7.31-7.27 (1H, m), 4.14 (2H, s), 4.12 (2H, s), 2.54 (1H , m), 1.16-1.13 (2H, m), 1.11-1 _09 (2H, m) Q acetic acid Example 12 (a carbonyl group {[(biphenyl-4-ylmethyl) -5-hydroxy-6-propyl-4-2- yl]})

(1) ({[6-allyl-5-(benzyloxy)-2-(biphenyl-4-ylmethyl)pyrimidin-4-yl]carbonyl}amino)acetate

-92- 200948788

Reference Example 5-(2) ({[5-(Benzyloxy)-2-(biphenyl-4-ylmethyl)-6-{[(trifluoromethyl)sulfonyl]oxy}) Pyrimidin-4-yl]carbonyl}amino)acetate (0.63 g, 1.0 mmol), 2·allyl-4,4,5,5-tetramethyl-1,3,2-di-n-boron Alkane (0.25 g, 1.5 mmol), sodium carbonate (0.32 g, 3.0 mmol) and dichlorobis(triphenylphosphine)palladium (0.070 g, 0.10 mm〇l) dissolved in tetrahydrofuran (3 mL) and water (1 · 5) (mL), heated under reflux for 4 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, the organic layer was extracted with ethyl acetate. After the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (Biotage, elution solvent: hexane/ethyl acetate), and Rf 値 = 0.30 ( hexane / ethyl acetate = 4 / The title compound (0.12 g, 0.23 mmol) (yield 23%) was obtained. 1H-NMR (500MHz, CDC13) (5: 8.33 (1H, m), 7.60-7.31 (14H, m), 6.82-6.78 (1 H, m), 6.27-6.22 (1H, m), 6.07-5.97 ( 1H, m), 5.10 (2H, s), 4.31 (2H, q, J = 8 Hz), 4.26 (2H, d, J = 8 Hz), 4.21 (2H, s), 3.58 (2H, d, J = 8 Hz), 1.31 (3H, t, J = 8 Hz) (2) (丨[2-(biphenyl-4-ylmethyl)-5-hydroxy-6-propylpyrimidin-4-yl] Ethyl carbonyl amide

Example 1-(3), using ({[6-allyl-5-(benzyloxy)-2-(biphenyl-4-ylmethyl)pyrimidin-4yl]carbonyl}amino) The title compound (0.080 g, 0.18 mmol) (yield: 80%). -93- 200948788 1H-NMR (500MHz, CDC13)5 : 11.38 (1H, s), 8.46 (1H, t, J = 4 Hz), 7.58-7.57 (2H, m), 7.54-7.52 (2H, m) , 7.43-7.38 (3H, m), 7.34-7.30 (2H, m), 4.27 (2H, q, J = 8 Hz), 4.23 (2H, s), 4.19 (2H, d, J = 4 Hz), 2.85 (2H, t, J = 4 Hz), 1.78 (2H, dt, J = 8 Hz, 4 Hz), 1.31 (3H, t, J = 8 Hz), 1.00 (3H, t, J = 8 Hz) . (3) ({[2-(Biphenyl-4-ylmethyl)-5-hydroxy-6-propylpyrimidin-4-yl]carbonylguanidino)acetic acid imitation Example 1-(4), with ( Ethyl acetate (0.06 g, 0.18 mmol g, 0.081 mmol) white solid (yield: 44%). 1H-NMR (400MHz, CD30D) 5 : 7.58-7.50 (4H, m), 7.41- 7.35 (4H, m), 7.31-7.27 (1H, m), 4.23 (2H, s), 4.13 (2H, s) , 2.83 (2H, t, J = 8 Hz), 1.76 (2H, dt, J = 8 Hz, 8 Hz), 0.98 (3H, t, J = 8 Hz). Example 13 [({2-[(3-chlorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

(1) 3-chlorobiphenyl-4-yl trifluoromethanesulfonate

Dissolve 3-chlorobiphenyl-4-ol (4.1 g, 20 mmol) in the dichlorocarbyl (50 200948788

After addition of diethylamine (4.0 mL, 24 mmol) in EtOAc (m.), EtOAc (EtOAc) An aqueous solution of sodium chloride was poured into the reaction mixture, and the organic layer was extracted with ethyl acetate. After the filtrate was concentrated under reduced pressure, the residue obtained was purified by silica gel column chromatography (Sen technology, solvent: hexane/ethyl acetate). Rf 値 = 52.52 (hexane/acetic acid B) The title compound (6.7 g, 20 mmol) was obtained (yield). lH-NMR (500MHz, CDC13) &lt;5: 7.72 (1H, d, J = 2 Hz), 7.56- 7.52 (3H, m), 7.47 (2H, t, J = 8 Hz), 7.43-7.41 (2H , m). (2) Methyl 3-chlorobiphenyl-4-carboxylate

Dissolve 3-chlorobiphenyl-4-yl trifluoromethanesulfonate (6.7 g, 20 mmol) in N,N-dimethylformamide (40 mL), add methanol (40 mL) and triethylamine (5.6 mL, 40 mmol). After the reaction mixture was degassed and replaced with nitrogen, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane (0.49 g, 0.60 mmol) was added. After the reaction mixture was again degassed and replaced with carbon monoxide (1 atmosphere), the reaction mixture was stirred at 60 ° C for 8 hours. The organic layer was extracted with ethyl acetate by adding water to the mixture. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After the filtrate was concentrated under reduced pressure, the obtained residue was purified by silica gel chromatography (yield: EtOAc/EtOAc). The title compound (4.3 g, 17-95-200948788 mmol) was obtained as white solid (yield 86%). lH-NMR (500MHz, CDC13) (5: 7.93 (1H, d, J = 8 Hz), 7.69 (1H, d, J = 2 Hz), 7.60 (2H, dd, J = 9 Hz, 2 Hz), 7.53 (1H, dd, J = 8 Hz, 2 Hz), 7.48 (2H, t, J = 7 Hz), 7.43 (1H, d, J = 9 Hz), 3.96 (3H, s). (3) ( 3-chlorobiphenyl-4-yl)methanol 〇Λ〇 将 3-chlorobiphenyl-4-carboxylic acid methyl ester (4.3 g, 17 mmol) dissolved in tetrahydrofuran (35 mL) over nitrogen After cooling to 0 ° C in an atmosphere, lithium aluminum hydride (0.65 g, 17 mmol) was stirred at the same temperature for 30 minutes. A few drops of water were added to the reaction mixture, and after vigorous stirring, the insoluble matter was filtered, and the filtrate was dried over anhydrous sodium sulfate. The solvent was evaporated to give crystals crystals crystals crystals crystalsssssssssssssssssssssssssssssssssss

7.54 (3H, m), 7.51 (1H, dd, J = 8 Hz, 2 Hz), 7.45 (2H, t, J = 8 Hz), 7.40.7.3 6 ( 1H, m). 4·84 (2H, d, J = 7 Hz). (4) 4-(Bromomethyl)-3-chlorobiphenyl

Br (3-chlorobiphenyl-4-yl)methanol (3.7 g, 17 mmol) was dissolved in tetrahydrofuran (35 mL), and phosphorus tribromide (〇·79 mL, 8.4 mmol) was added dropwise at 0 ° C under nitrogen atmosphere. Thereafter, the mixture was stirred at the same temperature for 20 minutes, and further stirred at room temperature for 5 hours. After the reaction mixture was added with water and the organic layer was extracted with ethyl acetate, the extract was washed with a saturated aqueous solution of sodium chloride, and the organic layer was dried over anhydrous sodium sulfate. After evaporation of the solvent -96- 200948788, the residue was purified by silica gel column chromatography (Sentech, solvent: hexane / ethyl acetate), and Rf 値 = 0.52 ( The title compound (4.7 g, 17 mmol)yield (yield: 98%). lH-NMR (500MHz, CDC13) δ: 7.63 (1H, d, J = 2 Hz), 7.56 (2H, d, J = 8 Hz), 7.51 -7.43 (4H, m), 7.38 (1H, t, J = 7 Hz). 4.64 (2H, s). 〇 (5) (3-chlorobiphenyl-4-yl)acetonitrile

Dissolve 4-(bromomethyl)-3-chlorobiphenyl (4.7 g, 17 mmol) in acetonitrile (40 mL) - water (4.0 mL), sodium cyanide (1.1 g, 22 mmol) and tetrabutyl bromide After a solution of the ammonium (0.53 g, 1-7 mmol), it was stirred at room temperature for 4 hours under a nitrogen atmosphere. After adding water and a saturated aqueous solution of sodium chloride to the mixture, the organic layer was extracted with ethyl acetate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (yield: hexane / ethyl acetate), and Rf 値 = 0.30 ( hexane / ethyl acetate = The title compound (3 6 g, 16 mmol) was obtained (yield: 95%). lH-NMR (500MHz, CDC13) 0 : 7.66 (1Η, d, J =: 2 Hz), 7.59-7.52 (4H, m), 7.46 (2H, t, J = 8 Hz), 7.40 (1H, t, J = 7 Hz), 3.88 (2H, s). (6) 2-(3-chlorobiphenyl-4-yl)ethylimidoamine acetate -97- 200948788

The title compound (2.0 g, 6.6 mmol) m.

lH-NMR (500MHz, CDC13) (5: 7.63 (1H, s), 7.56 (1H, d, J =7 Hz), 7.53-7.35 (5H, m), 7.26 (1H, d, J = 2 Hz) , 4.10 (2H, s), 3.97 (2H, s), 1.95 (3H, s) (7) 5-(Benzyloxy)-2-[(3-chlorobiphenyl-4-yl)methyl] -6-hydroxypyrimidine-4-carboxylic acid

Third butyl ester

The title compound (0.58 g, 1.1 mmol) was obtained as a white solid. (Yield 17%). Thin layer chromatography

Rf 値 = 0.25 (hexane/ethyl acetate = 2/1); MS m/z: 503 (M + H) + ;

lH-NMR (400MHz, CDC13) d : 9.72 (1H, br), 7.66 (1H, d, J = 2 Hz), 7.56-7.31 (12H, m), 5.25 (2H, s), 4.21 (2H, s ), 1.52 (9H, s). (8) [({5-(Benzyloxy)-2-[(3-chlorobiphenyl-4-yl)methyl]-6-hydroxypyrimidin-4-yl}carbonyl)amino]acetate- 98- 200948788

Reference Example 5_(2), using 3-(benzyloxy)-2-[(3-chlorobiphenyl-4-yl)methyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (0.86) The title compound (0.68 g, 1.3 mmol. lH-NMR (500MHz, CDC13) &lt;5: 8.02 (1H, t, J = 5 Hz), 7.67

(1H, d, J = 2 Hz), 7.59 -7.30 (1 2H, m), 5.36 (2H, s), 4.24 (2H, q, J = 7 Hz), 4.20 (2H, s), 4.15 (2H , d, J = 5 Hz), 1.30 (3H, t, J = 7 Hz). (9) ({[5-(Benzyloxy)-2-[(3-chlorobiphenyl-4-yl)methyl]-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidine -4-yl]carbonyl}amino)ethyl acetate

Reference Example 2-(3), using [({5-(benzyloxy)-2-[(3-chlorobiphenyl-4-yl)methyl]-6-hydroxypyrimidin-4-yl}carbonyl) The title compound (0.63 g, 0.95 mmol)yield (yield: 73%). lH-NMR (500MHz, CDC13) 5 : 8.11 (1H, t, J = 5 Hz), 7.66 (1H, d, J = 2 Hz), 7.58 (2H, d, J = 8 Hz), 7.51-7.43 ( 5H, m), 7.33-7.34 (5H, m), 5.24 (2H, s), 4.45 (2H, s), 4.25 (2H, q, J =7 Hz), 4.20 (2H, d, J = 5 Hz ), 2.45 (3H, s), 1.30 (3H, t, J = 7 Hz) 〇(l〇)[((5-(Benzyloxy)-2-[(3-chlorobiphenyl-4-yl)) Methyl]-6-methylpyrimidine-4-99-200948788-based carbonyl)amino]ethyl acetate

Reference Example 2-(4), using ({[5-(benzyloxychlorobiphenyl)methyl]-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidinyl]hydrazine Ethyl acetamide (0.63 g, 0.95 mmol) eluted MS m/z : 5 30 (M + H) + ; lH-NMR (500MHz, CDC13) 5 : 8.29 UH, 1 D = 6 Hz), 7.66

(1H, d, J = 2 Hz), 7.59 (2H, d, J = 8 Hz), 7.49-7.42 (5H, m), 7.40-7.33 (5H, m), 5.12 (2H, s), 4.44 ( 2H, s), 4.23 (2H, q, J =7 Hz), 4.18 (2H, d, J = 6 Hz), 2.45 (3H, s), 1.28 (3H, t, J =7 Hz). (ll) [({2-[(3-Chlorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyranosyl-4-yl)carbonyl)amino]acetate

EXAMPLE 1-(3) 'Use [({5-(benzyloxy)_2-[(3-chlorobiphenyl-4-yl)methyl)-6-methylpyrimidin-4-yl}carbonyl) Ethyl acetate ethyl ester (0.39 g, 0.73 mmol) eluted 1H-NMR (500MHz, CDC13) 5 : 11 ·37 (1Η, s), 8 _ 35 (1 Η, t, J 2 6 Hz), 7.64 (1H, d, J = 2 Hz), 7.58 (2H, d, J = 8 Hz), -100- 200948788 7.46-7.42 (3H, m), 7.36 (1H, t, J = 8 Hz), 7.30 (1H, d, J = 8 Hz), 4.38 (2H, s ), 4.26 (2H, q, J = 7 Hz), 4.16 (2H, d, J = 5 Hz), 2.54 (3H, s), 1.29 (3H, t, J = 7 Hz). (12) [({2-[(3-Chlorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid imitation Example 1-( 4), using [({2-[(3-chlorobiphenyl-4-yl)methyl)-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.39 g) The title compound (0.28 g, 0.68 mmol) m. 〇mp 1 8 2 °C ; MS m/z : 412 (M + H) + ; Calculated 値 analysis C21H1 8C1N304.1/4H20 : C, 60.58 ; Η, 4.48 ; N, 10.09 ; 0,16.33 ; Cl, 8.52 Measured 値: C, 60.34; H, 4.71; N, 9.82; 0, 16.36; Cl, 8.60; 1H-NMR (500MHz, CDC13) 5 : 11.28 (1H, s), 8.32 (1H, t, J = 6 Hz), 7.63 (1H, d, J = 2 Hz), 7.55 (2H, d, J = 8 Hz), Q 7.44-7.41 (3H, m), 7.35 (1H, tt, J = 8, 2 Hz) , 7.29 (1H, d, J 2 8 Hz), 4.38 (2H, s), 4.21 (2H, d, J = 6 Hz), 2.55 (3H, s). Example 1 4 [({2-[(3'-Fluorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-ylindole]amino)amino]acetic acid

(1) [({5-(Benzyloxy)-2-[(3'-fluorobiphenyl-4-yl)methyl]-6-hydroxypyrimidine-1-decyl}carbonyl)amino]acetate-101 - 200948788

Example 6-(1), obtained by reference Example 1-(4) ({[5-(benzyloxy)-2-(4-bromobenzyl)-6-hydroxypyrimidin-4-yl]carbonyl} Ethyl acetate (500 mg, 1.0 mmol) and (3-fluorophenyl)boronic acid (3 50 mg, 2.5 mmol) ). MS m/z : 516 (Μ + ΗΓ ; lH-NMR (400MHz, CDC13) &lt;5 : 8.06 (1H, t, J = 7 Hz), 7.54 (2H, d, J = 8 Hz), 7.50 (2H , d, J = 8 Hz), 7.41-7.29 (7H, m), 7.20 (1H, d, J = 9 Hz), 7.03 (2H, dt, J = 9 Hz, 3 Hz), 5.33 (2H, s ), 4.26 (2H, q, J = 7 Hz), 4.19 (2H, d, J = 7 Hz), 3.99 (2H, s), 1.31 (3H, t, J = 7 Hz). (2)[( {5-(Benzyloxy)-2-[(3'-fluorobiphenyl-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

Reference Example 2-(3), Reference Example 2-(4), using [({5-(benzyloxy)-2_[(3'-fluorobiphenyl-4-yl)methyl]-6-hydroxyl) The title compound (75 mg, 0.15 mmol MS m/z: 5 14 (M + H) + ; lH-NMR (400 MHz, CDC 13) (5: 8.34 (1H, t, J = 6 Hz), 7.53 (2H, d, J = 8 Hz), 7.47 (2H, d, J = 8 Hz), 7.45 (2H, d, J = 8 -102- 200948788

Hz), 7.39-7.23 (6H, m), 7.03-6.98 (1H, m), 5.09 (2H, s), 4.28 (2H, s), 4.26 (2H, q, J = 7 Hz), 4.22 (2H , d, J = 6 Hz), 2.46 (3H, s), 1.30 (3H, t, J = 7 Hz). (3) [({2-[(3'-fluorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetate

Example 1-(3), using [({5-(benzyloxy)-2-[(3'-fluorobiphenyl-4-yl)indolemethyl]-6-methylpyrimidin-4-yl) Ethyl acetate (75 mg, 0.15 mmol) EtOAc (m.

lH-NMR (400MHz, CDC13) 5 : 11.38 (1H, s), 8.46 (1H, t, J = 5 Hz), 7.51 (2H, d, J = 8 Hz), 7.41 (2H, d, J = 8 Hz), 7.35-7.25 (3H, m), 7.03-6.98 ( 1H, m), 4.27 (2H, q, J = 7 Hz), 4.22 (2H, s), 4.19 (2H, d, J = 5 Hz ), 2.53 (3H, s), 1.31 ❹ (3H, t, J = 7 Hz). (4) [({2-[(3'-Fluorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid imitation Example 1- (4), using [({2-[(3'-fluorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetate ( The title compound (23 mg, 0.058 mmol. Mp 201 °C; MS m/z: 396 (M + H) + ; 1H-NMR (400MHz, CDC13) &lt;5: 11.38 (1H, s), 8.46 (1H, t, -103- 200948788 J = 5 Hz), 7.50 (2H, d, J = 8 Hz), 7.41 (2H, d, J = 8 Hz), 7.37-7.21 (3H, m), 7.03-6.96 (1H, m), 4.22 (2H, s ), 4.19 (2H, d, J = 6 Hz), 2.53 (3H, s). Example 1 5 [({5-Hydroxy-2-[(3'-methoxybiphenyl-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid Ν^ 〇Η Ο

(1) ({[5-(Benzyloxy)-2-[(3methoxybiphenyl-4-yl)methyl]-6-{[(trifluoromethyl)sulfonyl]oxy} Pyrimidine-4-yl]carbonyl}amino)acetate NT^〇Bn °

Example 6-(1), Reference Example 2-(3), obtained by reference Example 1-(4) ({[5-(benzyloxy)-2-(4-bromobenzyl)-6-hydroxyl) Ethylpyrimidin-4-yl]carbonyl}amino)acetate (0.50 g, 1.0 mmol) and (3-methoxyphenyl)boronic acid (0.30 g, 2.0 mmol) Shaped substance (yield 31%). lH-NMR (500MHz, CDC13) 5 : 8.13 (1H, t, J = 5 Hz), 7.56 (2H, d, J = 8 Hz), 7.49 (2H, d, J = 7 Hz), 7.42 (2H, d, J= 8 Hz), 7.39-7.33 (4H, m), 7.17 (1H, d, J = 7 Hz), 7.11 (1H, s), 6.89 (1H, dd, J = 8 Hz, 2 Hz) , 5.22 (2H, s), 4.30-4.25 (4H, m), 4.22 (2H, d, J = 5 Hz), 3.86 (3H, s), 1.32 (3H, t, J = 7 Hz) » (2 )[({5-(Benzyloxy)-2-[(3'-methoxybiphenyl-4-yl)methyl]-6-methylpyrimidine-104- 200948788 pyridine-4-yl}carbonyl) Amino]ethyl acetate

Referring to Example 2-(4), using ({[5-(benzyloxy)-2-[(3'-methoxybiphenyl-4-yl)methyl]-6-{[(trifluoromethyl) The title compound (0.17 g, 0.31 mmol), m. ). lH-NMR (500MHz, CDC13) 5 : 8 · 3 4 (1 Η, t, J = 5 Hz), 7 · 5 5 (2H, d, J = 8 Hz), 7.48 (2H, d, J= 7 Hz), 7.44 (2H, d, J= 8 Hz), 7.39-7.32 (4H, m), 7.18-7.16 (1H, m), 7.12 (1H, t, J = 2 Hz), 6.88 (1H, dd , J = 8 Hz, 2 Hz), 5.09 (2H, s), 4.28 (2H, s), 4.26 (2H, q, J = 7 Hz), 4.22 (2H, d, J = 5 Hz), 3.86 ( 3H, s), 2.46 (3H, s), 1.31 (3H, t, J = 7 Hz). (3) [({5-Hydroxy-2-[(3'-methoxybiphenyl-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

仿 Example 1-(3), using [({5-(benzyloxy)-2-[(3'-methoxybiphenyl-4-yl)methyl]-6-methylpyrimidine-4 Ethyl acetate (0.17 g, 0.31 mmol), m. 1H-NMR (500MHz, CDC13) 5 : 11.38 (1H, s), 8.46 (1H, t,

J = 5 Hz), 7.53 (2H, d, J = 8 Hz), 7.40 (2H, d, J = 8 Hz), 7.33 (1H, t, J 2 Hz), 7.17 (1H, d, J = 7 Hz), 7.10 (1H,t,J -105- 200948788 =2 Hz), 6.87 (1H, dd, J = 8 Hz, 2 Hz), 4.28 (2H, q, J = 7 Hz), 4.22 (2H , s), 4.20 (2H, d, J 2 5 Hz), 3.85 (3H, s), 2.53 (3H, s). (4) [(5-Hydroxy-2-[(3'-methoxybiphenyl-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid imitation example 1-(4), using [({5-hydroxy-2-[(3'-methoxybiphenyl-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino] Ethyl acetate (110 mg, 0.25 mmol),jjjjjjjjjjjjjjjjjjjj (500MHz, CDC13) 5 : 11.29 (1H, s), 8.44 (1H, t, J = 5 Hz), 7.52 (2H, d, J = 8 Hz), 7.39 (2H, d, J = 8 Hz), 7.33 (1H, t, J = 8 Hz), 7.16-7.14 (1H, m), 7.10 (1H, t, J = 2 Hz), 6.87 (1H, ddd, J = 8, 2, 1 Hz), 4.27 (2H, d, J = 5 Hz), 4.23 (2H, s), 3.85 (3H, s), 2.54 (3H, s). Example 1 6 [({5-Hydroxy-6-methyl-2-[(3'-methylbiphenyl-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid

(1) [({5-Hydroxy-6-methyl-2-[(3'-methylbiphenyl-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetate-106 - 200948788 ο

Example 6-(1), Reference Example 2-(3), Reference Example 2-(4), Example Ιο), obtained by Reference Example 1-(4) ({[5-(Benzyloxy)-) Ethyl 2-(4-bromobenzyl)-6-hydroxypyrimidin-4-yl]carbonyl}amino)acetate (0.50 g, 1.0 mmol) and 3-tolylboronic acid (0.41 g, 2.0 mmol) Compound (0.11 g, 0.26 mmol) solid (yield 24%). MS m/z : 420 (M + H)+ ; Ο

lH-NMR (500MHz, CDC13) 5 : 11.38 (1Η, s), 8.47 (1H, t, J = 5 Hz), 7.51 (2H, d, J = 8 Hz), 7.39 (2H, d, J = 8 Hz), 7.24 (1H, s), 7.37 (1H, d, J = 7 Hz), 7.24 (1H, dd, J = 8 Hz, 7 Hz), 7.14 (1H, d, J = 8 Hz), 4.27 (2H, q, J = 7 Hz), 4.22 (2H, s), 4.18 (2H, d, J = 5 Hz), 2.53 (3H, s), 2.40 (3H, s), 1.31 (3H, t, J = 7 Hz). (2) [(5-Hydroxy-6-methyl-2-[(3'-methylbiphenyl-4-yl)methyl]pyrimidin-4-indolyl}carbonyl)amino]acetic acid imitation example 1-(4) with [({5-hydroxy-6-methyl-2-[(3'-methylbiphenyl-4-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid] Ethyl ester (0.11 g, 0.26 mmol) MS m/z: 392 (M + H).; lH-NMR (500MHz, DMSO-d6) δ: 7.50 (2H, d, J = 8 Hz), 7.38-7.34 (4H, m), 1.21 (1H, t, J = 7 Hz), 7.12 (1H, d, J = 7 -107- 200948788

Hz), 4.21 (2H, s)' 4.14 (2H, s), 2.49 (3H, s), 2.38 (3H, s). Example 17 ({[2-(2-biphenyl-4-ylethyl)·5·hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

(1) (3-biphenyl-4-yl)propanamidoacetate

Diethyl cyanomethylphosphonate (11 g, 60 mmol) was dissolved in tetrahydrofuran (80 mL), and a solution of lithium hexamethyldiazane in tetrahydrofuran (1 M, 65) was added at -78 ° C under nitrogen atmosphere. After a solution of mL, 65 mmol) and biphenyl-4-carbaldehyde (9.1 g, 50 mmol) in tetrahydrofuran (20 mL), 15 min. After the reaction solution was poured into water and extracted with ethyl acetate, the organic layer was dried over sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj This title compound (7.3 g, 26 mmol) Yield 79%). 1H-NMR (500MHz, DMSO-d6) &lt;5: 7.66-7.62 (4H, m), 7.48- 7.44 (3H, m), 7.37-7.33 (2H, m), 3.33 (2H, s), 2.96 ( 2H, t, J = 4 Hz), 2.63 (2H, t, J = 4 Hz), 1.65 (3H, s). (2) ({[5-(Benzyloxy)-2-(2-biphenyl-4-ylethyl)-6·{[(trifluoromethyl)sulfonyl]oxypyrimidine-4- Ethyl]carbonyl}amino)ethyl acetate-108- 200948788

Reference Example 1-(3), Reference Example 5-(2) '(3-Biphenyl-4-yl)propanamidoamine acetate (4.2 g, 15 mmol) 5.3 mmol) white solid (yield 35%). 1H-NMR (500MHz, CDC13) &lt;5 : 8.01 (1H, t, J = 4 Hz),

7.58-7.56 (2H, m), 7.53-7.49 (5H, m), 7.44-7.41 (2H, m), 7.39-7.32 (5H, m), 5.24 (2H, s), 4.25 (2H, q, J = 8 Hz), 4.18 (2H, d, J = 4 Hz), 3.32 (2H, t, J = 8 Hz), 3.18 (2H, t, J = 8 Hz), 1.31 (3H, t, J = 8 Hz). (3) ({[5-(Benzyloxy)-2-(2-biphenyl-4-ylethyl)-6-methylpyrimidin-4-yl]carbonyl}amino)ethyl acetate

Reference Example 2-(4) 'Use ({[5-(benzyloxy)-2-(2-biphenyl-4-ylethyl)-6-{[(trifluoromethyl)sulfonyl] Ethyloxypyrimidin-4-yl]carbonyl}amino)acetate (0.64 g, 1.0 mmol). 1H-NMR (500MHz, CDC13) 5 : 8.24 (1H, t, J = 4 Hz), 7.59-7.57 (2H, m), 7.53-7.52 (2H, m), 7.48-7.47 (2H, m), 7.44 -7.41 (2H, m), 7.39-7.31 (6H, m), 5.11 (2H, s), 4.25 (2H, q, J = 8 Hz), 4.19 (2H, d, J = 4 Hz), 3.28 ( 2H, t, J = 8 -109- 200948788

Hz), 3.20 (2H, t, J = 8 Hz), 2.45 (3H, s), 1.30 (3H, t, J = 8 Hz). (4) ({[2-(2-Biphenyl-4-ylethyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)ethyl acetate

Example 1-(3), using ({[5-(benzyloxy)-2-(2-biphenyl-4-ylethyl)-6-methylpyrimidin-4-yl]carbonyl}amino) The title compound (0.29 g, 0.68 mmol) (yield: 88%). 1H-NMR (500MHz, CDC13) &lt;5: 11.35 (1H, s), 8.42 (1H, t, J = 4 Hz), 7.59-7.58 (2H, m), 7.53-7.51 (2H, m), 7.44 -7.41 (2H, m), 7.34-7.32 (3H, m), 4.26 (2H, q, J = 8 Hz), 4.18 (2H, d, J = 4 Hz), 3.24-3.21 (2H, m), 3.17-3.14 (2H, m), 2.54 (3H, s), 1.32 (3H, t, J = 8 Hz). (5) ({[2-(2-biphenyl-4-ylethyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid imitation Example 1-(4), Ethyl ({[2-(2-biphenyl-4-ylethyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonylguanidino)acetate (0.29 g, 0.68 mmol) The title compound (0.24 g, 0.62 mmol. Mp 184-1B5 °C ; 1H-NMR (500MHz, CD30D) δ : 7.58-7.56 (2Η, m), 7.51- 7.50 (2H, m), 7.41-7.38 (2H, m), 7.31-7.28 (3H, m), 4.13 (2H, s), 3.18 (4H, m), 2.49 (3H, s). -110- 200948788 Example 1 8 ({[2-(4·T-butylbenzyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino) ruthenium acetate (1) (4-third Butyl phenyl) acetonitrile

Example 13-(5), 1-(bromomethyl)-4-t-butylbenzene (5.0 g, 0.022 mol). Rate 95%). lH-NMR (400MHz, CDC13) ¢5 : 7.40 (2H, d, J = 8 Hz), 7.26 (2H, d, J = 8 Hz), 3.72 (2H, s), 1·32 (9H, s) . (2) tert-butyl 5-(benzyloxy)-2-(4-tert-butylbenzyl)-6-hydroxypyrimidine-4-carboxylate

The title compound (4.2 g, 9.4 mmol) was obtained as a white solid (m.). The rate is 47%). Thin layer chromatography Rf 値 = 0.25 (hexane / ethyl acetate = 1 / 1); MS m / z: 449 (M + H) + ; lH-NMR (400 MHz, CDC13) 5 : 7.45 (2H, d, J = 7 Hz), 7.41 (2H, d, J = 8 Hz), 7.37-7.31 (3H, m), 7.21 (2H, d, J = 8 Hz), -Ill - 200948788 5.24 (2H, s), 4·〇1 (2H, s), 1.53 (9H, s), 1.33 (9Η, s). (3) tert-butyl 5-(benzyloxy)-2-(4-tert-butylbenzyl)-6-methylpyrimidine-4-carboxylate

Reference Example 2-(3), Reference Example 2-(4), using 3-(benzyloxy)-2-(4-t-butylbenzyl)-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester ( The title compound (1.7 g, 3.8 mmol. Thin layer chromatography Rf 値 = 0.30 (hexane / ethyl acetate = 5 / 1); lH-NMR (400 MHz, CDC13) 5 : 7.42-7.30 (9H, m), 4.97 (2H, s), 4.22 (2H , s), 2.44 (3H, s), 1.57 (9H, s), 1.33 (9H, s) » (4) ({[5-(benzyloxy)-2-(4-t-butylbenzyl)-6) -methylpyrimidin-4-yl]carbonyl}amino)ethyl acetate

Dissolving the third butyl 5-(benzyloxy)-2-(4-t-butylbenzyl)-6-methylpyrimidine-4-carboxylate (1.7 g, 3-8 mmol) in methanol (30 mL) and tetrahydrofuran ( 1 〇mL) of the mixed solvent, adding sodium hydroxide aqueous solution (8 M, 3.8 mL, 30 mmol), and stirring at 80 ° C for 2 hours. After the reaction mixture was cooled to room temperature, hydrochloric acid (2 Μ, 19 mL, 38 mmol), the organics were extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium chloride, and then evaporated to vacuo to give 5-(benzyloxy)-2-(4-tributylbenzyl)-6-methylpyrimidine-4-carboxylic acid (1.5 g, 3.8 mmol) white solid (quantitative yield). -112- 200948788 MS m/z : 391 (M + H) + _ 〇

5-(Benzyloxy)-2-(4-tert-butylbenzyl)-6-methylpyrimidine-4-carboxylic acid (0.40 g, 1.0 mmol), ethyl acetate (0.27 g, 1.9 Ment), (1Η-benzotriazol-1·yloxy)(tripyrrolidin-i.yl)iron hexafluorophosphate (PyBOP) (ll g, 2.0 mmol), triethylamine (0.56 mL, 4.0 Methyl) was dissolved in N,N-dimethylformamide (5.0 mL) and stirred at 100 ° C for 2 h. Water was poured into the reaction mixture, the organic layer was extracted with ethyl acetate, and the organic layer was washed with aqueous sodium chloride. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (yield: hexane/ethyl acetate), and Rf 値 = 0.58 (hexane/ethyl acetate = The title compound (0.46 g, 0.97 mmol) of white solid (yield 97%). Thin layer chromatography Rf 値 = 0.58 (hexane / ethyl acetate = 2 / 1); MS m/z: 475 (M + H) + ; lH-NMR (40 〇 MHz, CDC13) δ 8.34 (1H, t , J = 5 Hz), 7.48 (2H, d, J = 8 Hz), 7.40-7.29 (7H, m), 5.08 (2H, s), 4.27 (2H, q, J = 7 Hz), 4.22 (2H , d, J = 5 Hz), 4.21 (2H, s), 2.45 (3H, s), 1.33 (3H, t, J = 7 Hz), 1.31(9H, s). (5) ({[2-(4-Tertibenzyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonylguanidinyl) ethyl acetate

Example 1-(3), using ({[5-(benzyloxy)-2-(4-t-butylbenzyl)-6-methylpyrimidin-4-yl)carbonyl}amino)acetate ( 460 mg, 0.97 mm ο 1), get -113- 200948788

The title compound (390 mg, 1.0 mmol). lH-NMR (400MHz, CDC13) &lt;5: 11.35 (1H, s), 8.46 (1H, t, J = 5 Hz), 7.32 (2H, d, J = 9 Hz), 7.27 (2H, d, J = 9 Hz), 4.28 (2H, q, J 2 7 Hz), 4.19 (2H, d, J = 5 Hz), 4.15 (2H, s), 2.52 (3H, s), 1_32 (3H, t, J = 7 Hz), 1_29 (9H, s). (6) ({[2-(4-Tertibutylbenzyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid imitation Example 1-(4), using ({[2 Ethyl -4-(t-butylbenzyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (390 mg, 1.0 mmol). Methyl) white solid (yield 80%). m p 162 ° C ; MS m/z : 3 5 8 (M + H) + ; Calculated 値 analysis C19H23N304 : C, 63.85; Η, 6.49 ;

11.76. Measured 値: C, 63.71 ; Η, 6.42 ; Ν, 11.69 ; lH-NMR (400MHz, CDC13) (5: 11.26 (1H, s), 8.44 (1H, t, J = 6 Hz), 7.32 (2H , d, J = 9 Hz), 7.27 (2H, d, J = 9 Hz), 4.28 Q (2H, d, J = 6 Hz), 4.16 (2H, s)' 2.52 (3H, s), 1.29 ( 9H, s). Example 1 9 (S)-2-({ [2-(biphenyl-4-ylmethyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl} Amino) Propionic acid

(1) 5-(Benzyloxy)-2-(biphenyl-4-ylmethyl)-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidine-4-carboxylic acid tertidine Ester-114- 200948788

Reference Example 2 - (3), using Reference Example 5 · (1) 5-(Benzyloxy)-2 -(biphenyl-4-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid Butyl ester (3.2 g, 8.0 mmol) was obtained as the title compound (3.2 g, 5.3 mmol) (yield: 66%). lH-NMR (500MHz, CDC13)5: 7.58-7.54 (4H, m), 7.46-7.32 (10H, m), 5.11 (2H, s), 4·29 (2H, s), 1.56 (9H, s) . Ο (2) 5-(benzyloxy)-2-(biphenyl-4-ylmethyl)-6-methylpyrimidine-4-carboxylic acid tert-butyl ester

Referring to Example 2-(4), 5-(benzyloxy)-2-(biphenyl-4-ylmethyl)-6-{[(trifluoromethyl)sulfonyl]oxypyrimidine- 4-carboxylic acid tert-butyl ester (3.2 g, 5.3 mmol) gave the title compound (1, 2 g, 2.6 mmol) as an amorphous solid (yield 50%). MS m/z : 405 (M + H) + ; lH-NMR (500MHz, CDC13) 5 : 7.58 (2H, d, J = 8 Hz), 7.53 (2H, d, J = 8 Hz), 7.47 (2H , d, J = 7 Hz), 7.44-7.31 (8H, m), 4.96 (2H, s), 4.30 (2H, s), 2.45 (3H, s), 1.59 (9H, s). (3) (S)-2-({[5-(Benzyloxy)-2-(biphenyl-4-ylmethyl)-6-methylpyrimidin-4-yl]carbonyl}amino)propionic acid Methyl ester

-115- 200948788 Reference Example 1-(4) 'Used 3-(benzyloxy)-2-(biphenyl-4-ylmethyl)-6-methylpyrimidine-4-carboxylic acid tert-butyl ester ( The title compound (0.47 g, 0.96 mmol), m. MS m/z: 496 (M + H) + ; lH-NMR (500MHz, CDC13) &lt;5: 8.36 (1H, t, J = 8 Hz), 7.58

(2H, d, J = 8 Hz), 7.56 (2H, d, J = 8 Hz), 7.48-7,33 (1 0H, m), 5.12 (1H, d, J = 11 Hz), 5.06 (1H , d, J = 11 Hz), 4.75 (1H, quint, J = 7 Hz), 4.30 (2H, s), 3.78 (3H, s), 2.45 (3H, s), 1.52 (3H, d, J II 7 Hz). (4) (S)-2-({[2-(biphenyl-4-ylmethyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)propionic acid methyl ester

Example 1-(3), using (S)-2-({[5-(benzyloxy)-2-(biphenyl-4-ylmethyl)-6-methylpyrimidin-4-yl] Carbonyl}amino)propionic acid methyl ester (0.47 g, 0.96 mmol) gave the title compound (0.35 g, lH-NMR (500MHz, CDC13) &lt;5: 11.44 (1H, s), 8.48 (1H, t, J = 8 Hz), 7.58 (2H, dd, J = 8 Hz, 1 Hz), 7.54 (2H, d, J = 8 Hz), 7.44-7.41 (4H, m), 7.33 (1H, t, J = 7 Hz), 4.70 (1H, quint, J = 7 Hz), 4.24 (2H, s), 3.81 ( 3H, s), 2.53 (3H, s), 1.56 (3H, d, J = 7 Hz). (5) (S)-2-({[2-(biphenyl-4-ylmethyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)propionic acid-116- 200948788 Example 1-(4), using (S)-2-({[2-(biphenyl-4-ylmethyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino) Methyl propionate (0.35 g, 0.89 mmol) gave the title compound (0.32 g, Mp 1 85 - 1 86 ° C ; Calculated 値 analysis C22H21N304 : C, 67.51 ; H, 5.41 ; N, 10.74. Measured 値: C, 67.30 ; H, 5.35 ; N, 10.76; lH-NMR (500 MHz, DMSO-d6 ) &lt;5 : 13.00 (1H, s), 11.93 (1H, 〇s), 9.31 (1H, t, J = 7 Hz), 7.63 (2H, d, J = 8 Hz), 7.59 (2H, d, J = 8 Hz), 7.47-7.33 (5H, m), 4.51 (1H, quint, J = 7 Hz), 4.21 (2H, s), 2.43 (3H, s), 1.48 (3H, d, J = 7 Hz). Example 20 [({2-[(3'-Cyanobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

(1) [({5-(Benzyloxy)-2-[(3'-cyanobiphenyl-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid] Ethyl ester

Example 6-(1), ({[5-(benzyloxy)-6.methyl-2-(4-{[(trifluoromethyl)sulfonyl)oxy) obtained by Reference Example 3 Ethyl benzyl)pyrimidin-4-yl]carbonyl}amino)acetate (〇.2 〇g, 0.35 mmol) and 3-cyanophenylboronic acid (1. g, 0.11 mmol) light yellow oil - 117 - 200948788 (yield 31%). MS m/z : 521 (M + H) + ; lH-NMR (500MHz, CDC13) 5 : 8.32 (1H, t, J = 5 Hz), 7.88 (1H, s), 7.80 (1H, m), 7.61 (1H, m), 7.55-7.34 (1 0H, m), 5.10 (2H, s), 4.30 (2H, s), 4.27 (2H, q, J = 7 Hz), 4.21 (2H, d, J = 5 Hz), 2.46 (3H, s), 1.32 (3H, t, J = 7 Hz). (2) [({2-[(3'-Cyanobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

Example 1-(3), using [({5-(benzyloxy)-2-[(3'-cyanobiphenyl-4-yl)methyl]-6-methylpyrimidin-4-yl) Ethyl acetate (0.057 g, 0.11 mmol) EtOAc (m. MS m/z : 43 1 (M + H)+ ;

lH-NMR (500MHz, CDC13) 5 : 11.39 (1H, s), 8.44 (1H, t, J

=6 Hz), 7.86 (1H, s), 7.79 (1H, d, J = 8 Hz), 7.61 (1H, d, J 2 7 Hz), 7.53 (1H, dd, J 2 8 Hz, 7 Hz) , 7.51 (2H, d, J 2 8

Hz), 7.45 (2H, d, J = 8 Hz), 4.29 (2H, q, J = 7 Hz), 4.24

(2H, s), 4.19 (2H, d, J = 6 Hz), 2.54 (3H, s), 1.33 (3H, t, J =7 Hz). (3) [({2-[(3'-Cyanobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid-118- 200948788 Example 1-(4), using [({2-[(3,-cyanobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amine Ethyl acetate (0.036 g, 0.084 mmol). MS m/z : 403 (M + H) + ; lH-NMR (500MHz, DMSO-d6) &lt;5: 12.89 (1H, s), 11.97 (1H, 〇s), 9.49 (1H, t, J = 6 Hz), 8.13 (1H, s), 7.99 (1H, d, J = 8 Hz), 7.81 (1H, d, J = 7 Hz), 7.67 (2H, d, J = 8 Hz), 7.65 (1H , dd, J = 8 Hz, 7 Hz), 7.44 (2H, d, J = 8 Hz), 4.21 (2H, s), 4.01 (2H, d, J = 6 Hz), 2.43 (3H, s). Example 21 {[(2-{[3'-(Benzyloxy)biphenyl-4-yl]methyl}-5-hydroxy-6-methyl-pyrimidin-4-yl)carbonyl]amino}acetic acid

(1) ({[5-(Benzyloxy)-2-{[3'-(benzyloxy)biphenyl-4-yl]methyl b 6-methylpyrimidin-4-yl]carbonyl}amino group Ethyl acetate

Example 6-(1), ({[5-(benzyloxy)-6-methyl-2-(4-{[(trifluoromethyl)sulfonyl)oxy) obtained with Reference Example 3 Ethyl acetate (0.20 g, 0.35 mmol) and 3-(benzyloxy)phenylboronic acid (0.16 g, 0.70 mmol) , 0.27 mmol) pale yellow-119- 200948788 color oily substance (yield 76%). MS m/z : 602 (M + H) + ; lH-NMR (500MHz, CDC13) (5: 8.34 (1H, t, J = 5 Hz), 7.54- 7.18 (17H, m), 6.96-6.94 (1H , m), 5.11 (2H, s), 5.09 (2H, s), 4.28 (2H, s), 4.26 (2H, d, J = 5 Hz), 4.22 (2H, q, J = 7 Hz), 2.46 (3H, s), 1.30 (3H, t,; i = 7 Hz). (2) {[(2-{[3'-(Benzyloxy)biphenyl-4-yl]methyl}-5- Ethyl hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}ethyl acetate

Example M3), using ({[5-(benzyloxy)-2-{[3'-(benzyloxy)biphenyl-4-yl]methyl}-6-methylpyrimidin-4-yl) Ethyl acetate (0.15 g, 0.26 mmol), m. MS m/z: 512 (M + H)+ ;

lH-NMR (500MHz, CDC13) &lt;5: 11.38 (1H, s), 8.45 (1H, t, J = 5 Hz), 7.52-7.17 (12H, m), 6.96-6.93 ( 1 H, m), 5.11 (2H, s), 4.27 (2H, q, J = 7 Hz), 4.22 (2H, s), 4.19 (2H, d, J = 5 Hz), 2.53 (3H, s), 1.31 (3H, t , J = 7 Hz). (3) {[(2-{[3*-(Benzyloxy)biphenyl-4-yl]methyl) 5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid imitation Example 1-(4), using {[(2-{[3'-(benzyloxy)biphenyl-4-yl]methyl}- 5-hydroxy-6-methylpyrimidin-4-yl)carbonyl] The title compound (0.022 g, 0.046 mmol) of white crystals (yield: 77%). MS m/z: 484 (M + H) + ; lH-NMR (500 MHz, DMSO-d6) &lt;5: 12.88 (1H, s), 11.97 (1H, s), 9.48 (1H, t, J = 6 Hz), 7.59-7.32 (1 0H, m), 7.24-7.19 (2H, m), 7.00-6.98 (1H, m), 5.17 (2H, s), 4.19 (2H, s), 4.01 (2H, d , J = 6 Hz), 2.43 (3H, s). Example 22 [({2-[4-(Cyclohexyloxy)benzyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid hydrazine (1) [({5 -(Benzyloxy)-2-[4-(cyclohexyloxy)benzyl]-6-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

({[5-(Benzyloxy)-2-(4-hydroxybenzyl)-6-methylpyran-4-yl]indenyl}amino)acetic acid ethyl acetate obtained in Reference Example 2-(5) A solution of the ester (0.15 g, 0.34 mmol) in tetrahydrofuran (5 mL) - cyclohexanol (0.069 g, 0.69 mmol), triphenylphosphine (0-18 g, 0.69 mmol) and diethyl azodicarboxylate The solution (2.2 M, 0.31 mL, 0. 69 mmol) was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent solvent: hexane/ethyl acetate), and Rf 値 = 0.65 (hexane/ethyl acetate = The title compound was obtained as a pale yellow oily material (yield: 38%). MS m/z: 518 (M + H)+. (2) [({2-[4-(Cyclohexyloxy)benzyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid imitation Example 1-(3) , using [({5-(benzyloxy)-2-[4-(cyclohexyloxy)benzyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.059 g) The title compound (0.055 g, 0.13 mmol) m. MS m/z : 428 (M + H).;

lH-NMR (500MHz, CDC13) δ 11.35 (1Η, s), 8.34 (1H, t, J = 5 Hz), Ί .22 (2H, d, J = 9 Hz), 6.83 (2H, d, J = 9 Hz), 4.27 (2H, q, J = 7 Hz), 4.21-4.16 (1H, m), 4.19 (2H, d, J = 5 Hz), 4.11 (2H, s), 2.51 (3H, s) , 2.00-1.95 (2H, m), 1.83-1.76 (2H, m), 1.60- 1.45 (3H, m), 1.37- 1.25 (3H, m), 1.32 (3H, t, J = 7 Hz). (3) [({2-[4-(Cyclohexyloxy)benzyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]]acetic acid imitation Example 1-(4), Using [({2-[4-(cyclohexyloxy)benzyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.055 g, 0.13 mmol) The title compound (0.031 g, EtOAc. lH-NMR (500MHz, DMSO-d6)5: 11.93 (1H, s), 9.45 (1H, t, J = 6 Hz), 7.19 (2H, d, J = 8 Hz), 6.83 (2H, d, J = 8 Hz), -122- 200948788 4.27-4.24 (1H,m),4.05 (2H,s), 4.00 Gil,d' J = 6 Hz),2.41 (3H,s),1.92-1.86 (2H,m ), 1.70-ι·65 (2H, m), 1.55-1.47 (1H, m), 1.41-1.23 (5H, m). Example 23 [({2·[4-(Hexyloxy)benzyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

Ο (1) [({5-(Benzyloxy)-2-[4-(hexyloxy)benzyl])-methylpyrimidin-4-yl}carbonyl)amino]acetate

Example 22-(1) '({ [5-(Benzyloxy)-2-(4-hydroxybenzyl)-6-methylpyrimidin-4-yl)carbonyl) was obtained using Reference Example 2-(5) Ethyl acetate, EtOAc (5 g, EtOAc, EtOAc, EtOAc, EtOAc (EtOAc) Yield 41%). MS m/z : 520 (M + H)+. (2) [({2-[4-(Hexyloxy)benzyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid imitation Example 1-(3) With [({5-(benzyloxy)-2-[4-(hexyloxy)benzyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.073 g, 0.14 The title compound (0.060 g, 0.14 mmol) was obtained as a colorless oil (yield -123- 200948788

lH-NMR (500MHz, CDC13) 5 : 11.34 (1H, s), 8.45 (1H, t, J = 5 Hz), 7.23 (2H, d, J = 9 Hz), 6.82 (2H, d, J = 9 Hz), 4.28 (2H, q, J = 7 Hz), 4.19 (2H, d, J = 5 Hz), 4.11 (2H, s), 3.91 (2H, t, J = 6 Hz), 2.51 (3H, s), 1.78- 1.72 (2H, m), 1.46-1.40 (2H, m), 1.34- 1.30 (4H, m), 1.32 (3H, t, J = 7 Hz), 0.89 (3H, t, J = 7 Hz). (3) [({2-[4-(Hexyloxy)benzyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid imitation Example 1-(4), [({2-[4-(Hexyl)benzyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.060 g, 0.14 mmol) (0.030 g, 0.078 mmol) white solid (yield: 56%). lH-NMR (500MHz, DMSO-d6) 5 : 12.98 (1H, s), 11.94 (1H, s), 9.45 (1H, t, J = 6 Hz), 7.20 (2H, d, J = 9 Hz), 6.83 (2H, d, J = 9 Hz), 4.06 (2H, s), 4.00 (2H, d, J = 6 Hz), 3.90 (2H, t, J = 6 Hz), 2.41 (3H, s), 1.70- 1.64 (2H, m), 1.41-1.35 (2H, m), 1.32-1.20 (4H, m), 0.86 (3H, t, J = 7 Hz). Example 24 ({[2-(4-cyclohexyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

(1) (丨[5-(Benzyloxy)-2-(4-cyclohex-1-ene-; 1-benzyl)-6-methylpyrimidin-4-yl]-124- 200948788 carbonyl}amine Ethyl acetate

Example 6-(1), ({[5-(benzyloxy)-6-methyl-2-(4-{[(trifluoromethyl)sulfonyl)oxy) obtained with Reference Example 3 Benzyl)pyrimidin-4-yl]carbonyl}amino)acetate (0.69 g, 1.2 mmol) and 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl -1,3,2-Dioxaborane (0.38 g, 1.8 mmol). MS m/z: 500 (M + H)+. (2) ({ [2-(4-cyclohexyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonylguanidino) ethyl acetate imitation Example 1-(3), {[5-(Benzyloxy)-2-(4-cyclohex-1-en-1-yl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0-13 g, The title compound (0.09 5 g, 0.23 mmol). MS m/z: 412 (M + H)+ ;

lH-NMR (500MHz, CDC13) 5 : 11.35 (1H, s), 8.46 (1H, t, J = 6 Hz), 7.25 (2H, d, J = 8 Hz), 7.14 (2H, d, J = 8 Hz), 4.28 (2H, q, J = 7 Hz), 4.19 (2H, d, J = 6 Hz), 4.14 (2H, s), 2.51 (3H, s), 2.48-2.43 (1H, m), 1.85-1.81 (4H, m), 1.74-1.72 (1H, m), 1.43 - 1.22 (5H, m), 1.32 (3H, t, J = 7 Hz). (3) ({ [2-(4-cyclohexyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)-125- 200948788 acetic acid imitation Example 1-(4), Ethyl ({[2-(4-cyclohexyl)-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl}amino)acetate (0.095 g, 0.23 mmol) g, 0.18 mmol) white solid (yield: 79%). MS m/z : 384 (M + H) + ; lH-NMR (500MHz, DMSO-d6) 5 : 12.89 (1H, s), 1 1.95 (1H, s), 9.45 (1H, t, J = 6.3 Hz ), 7.21 (2H, d, J = 7.8 Hz), 7.12 (2H, d, J = 7.8 Hz), 4.09 (2H, s), 4.00 (2H, d, J = 6.3 Hz), 2.43-2.40 (1H , m), 2.41 (3H, s), 1.85- 1.65 (5H, m), 1.40-1.15 (5H, m). Example 25 {[(5-Hydroxy-6-methyl-2-{[3'-(trifluoromethoxy)biphenyl-4-yl]methyl}pyrimidin-4-yl)carbonyl]amino} Acetic acid.

(1) ({[5-(Benzyloxy)-6-methyl-2-{[3'-(trifluoromethoxy)biphenyl-4-yl]methyl}pyrimidin-4-yl]carbonyl) Ethyl acetate

Example 6-(1), ({[5-(benzyloxy)-6-methyl-2-(4-{[(trifluoromethyl)sulfonyl)oxy) obtained with Reference Example 3 Ethyl acetate, benzyl)pyrimidin-4-yl]carbonyl}amino)acetate (0.30 g, 0.53 mmol) 〇_48 mmol) Light yellow-126- 200948788 Color oily substance (yield 91%). MS m/z : 580 (M + H) + ; lH-NMR (500MHz, CDC13) 5 : 8.34 (1H, t, J = 5 Hz), 7.54- 7.34 (12H, m), 7.19-7.17 (1H, m), 5.09 (2H, s), 4.29 (2H, s), 4.26 (2H, q, J = 7 Hz), 4.21 (2H, d, J = 5 Hz), 2.46 (3H, s), 1.31 ( 3H, t, J = 7 Hz). (2) {[(5-Hydroxy-6-methyl-2-{[3'-(trifluoromethoxy)biphenyl-4-yl]methyl}pyrimidin-4-yl)carbonyl]amino} Ethyl acetate imitation of Example (3) with ({[5-(benzyloxy)-6-methyl-2-{[3'-(trifluoromethoxy)biphenyl-4-yl]-) Ethyl acetate (0.28 g, 0.48 mmol) m.

lH-NMR (500MHz, CDC13) 5 : 11.38 (1H, s), 8.45 (1H, t, J 〇 = 5 Hz), 7.52-7.49 (3H, m), 7.45-7.42 (4H, m), 7.18- 7.17 (1H, m), 4.27 (2H, q, J = 7 Hz), 4.23 (2H, s), 4.19 (2H, d, J = 5 Hz), 2.53 (3H, s), 1.32 (3H, t , J = 7 Hz). (3) {[(5-Hydroxy-6-methyl-2-{[3'-(trifluoromethoxy)biphenyl-4-yl]methyl}pyrimidin-4-yl)carbonyl]amino} Example 1-(4) of acetic acid, using {[(5-hydroxy-6-methyl-2-{[3'-(trifluoromethoxy)biphenyl-4-yl]methyl}pyrimidine-4 Ethyl-carbonyl]amino}acetate (0.18 g, 0.36 mmol) MS m/z: 462 (M + H).; lH-NMR (500MHz, DMSO-d6) &lt;5: 11.97 (1H, s), 9.50 (1H, t, J = 6 Hz), 7.69 (1H, d, J = 7 Hz), 7.64 (2H, d, J = 8 Hz), 7.60 (1H, s), 7.58 (1H, dd, J = 8 Hz, 7 Hz), 7.43 (2H, d, J = 8 Hz), 7.34 (1H, d, J = 8 Hz), 4.20 (2H, s), 4.02 (2H, d, J = 6 Hz), 2_43 (3H, s). Example 26 ({[2-(4-cyclohex-1-en-1-ylbenzyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

U)({[2-(4-cyclohex-1-yoth-1-yl))-5-trans-yl.6-methylammonium _4.yl]hydrazino}amino)ethyl acetate will be implemented Example 24-(1) ({[5-(Benzyloxy)_2_(4-cyclohex-1-en-1-yl)-6-methylcvdin-4-yl]carbonyl}amino group Ethyl acetate (〇19 g, 0.38 mmol) was dissolved in ethanol (1 mL), concentrated hydrochloric acid (5.0 mL), and then stirred at 5 (TC) for 8 hours. After the reaction mixture was concentrated under reduced pressure, the residue was obtained. Refining by silica gel column chromatography (Sen Technology Co., Ltd., solvent: hexane/ethyl acetate), and decompressing the fraction corresponding to Rf 値 = 0.75 (hexane/ethyl acetate = 2/1) of thin layer chromatography. The title compound (〇15 g, 0.37 mm 〇1) solid (yield: 96%) was obtained.. -128-200948788 MS m/z: 410 (M + H) + ;

lH-NMR (500MHz, CDC13) &lt;5: 11.36 (1H, s), 8.45 (1H, t, J = 5 Hz), 7.31 (2H, d, J = 8 Hz), 7.26 (2H, d, J = 8 Hz), 6.09 (1H, m), 4.27 (2H, q, J = 7 Hz), 4.18 (2H, d, J = 5 Hz), 4.16 (2H, s), 2.51 (3H, s), 2.40-2.35 (2H, m), 2.22-2.16 (2H, m), 1.76- 1.73 (2H, m), 1.66- 1.63 (2H, m), 1.32 (3H, t, J = 7 Hz) o 〇( 2) ({[2-(4-Cyclohex-1-en-1-ylbenzyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid imitation Example 1-( 4), using ({[2-(4-cyclohex-1-en-1-ylbenzyl)-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl}amino)acetate (0.15 The title compound (0.080 g, 0.21 mmol. MS m/z : 382 (M + H) + ; lH-NMR (500MHz, DMSO-d6) (5: 12.88 (1H, s), 11.96 (1H, s), 9.45 (1H, t, J = 5 Hz ), 7.31 (2H, d, J = 8 Hz), 7.24 (2H, Q d, J = 8 Hz), 6.10 (1H, s), 4.12 (2H, s), 4.00 (2H, d, J = 5 Hz), 2.41 (3H, s), 2.34-2.30 (2H, m), 2.18-2.13 (2H, m), 1.72- 1.67 (2H, m), 1.60-1.56 (2H, m). Example 27 ( {[5-Hydroxy-6-methyl-2-(4-phenoxybenzyl)pyrimidin-4-yl]carbonyl}amino)acetic acid

(1) 2-(4-Phenoxyphenyl)ethylimidoamine acetate-129- 200948788 IH AcOH LNH2 〇r°〇Ji Refer to Reference Example 4-(4) with (4-phenoxyphenyl) The title compound (1.1 g, 3.9 mmol) m. 1H-NMR (400MHz, CD30D) (5: 7.38-7.33 (4H, m), 7.15- 7.12 (IH, m), 7.00-6.98 (4H, m), 3.75 (2H, s), 1.89 (3H, s o (2)({ [5-(Benzyloxy)-6-methyl-2-(4-phenoxybenzyl)pyrimidin-4-yl]carbonyl}amino)ethyl acetate

Reference Example 1-(3), Reference Example 5-(2), Reference Example 2-(4), using 2-(4-phenoxyphenyl)ethyliminoamine acetate (1.1 g, 3.9 mmol) The title compound (0.12 g, 0.24 mmol). 1H-NMR (500MHz, CDC13) &lt;5: 8.33 (1H, t, J = 4 Hz), 7.48-7.30 (9H, m), 7.09 (1H, t, J = 8 Hz), 7.00 (2H, d , J = 4

Hz), 6.96 (2H, d, J = 8 Hz), 5.10 (2H, s), 4.26 (2H, q, J = 8

Hz), 4.22 (2H, d, J = 4 Hz), 4.22 (2H, s), 2.46 (3H, s), 1.31 (3H, t, J = 8 Hz). (3) ({ [5-Hydroxy-6-methyl-2-(4-phenoxybenzyl)pyrimidin-4-yl]carbonylguanidinyl) ethyl acetate imitation Example 1-(3), used ( {[5-(Benzyloxy)-6-methyl-2-(4-phenoxybenzyl)pyrimidin-4-yl]carbonyl}amino)acetate (0.12 g, 0.24 mmol) 130- 200948788 Compound (0.079 g, 0.19 mmol) (yield: 79%). 1H-NMR (500MHz, CDC13) &lt;5: 11.38 (1H, s), 8.45 (1H, t, J = 4 Hz), 7.33-7.29 (4H, m), 7.08 (1H, t, J = 4 Hz ), 6.98 (2H, d, J = 8 Hz), 6.95 (2H, d, J = 8 Hz), 4.28 (2H, q, J = 8

Hz), 4.20 (2H, d, J = 4 Hz), 4.16 (2H, s), 2.53 (3H, s), 1.32 (3H, t, J = 8 Hz). (4) ({ [5-Hydroxy-6-methyl-2-(4-phenoxybenzyl)pyrimidin-4-yl]carbonyl}amino)acetic acid

Example 1-(4), using ({[5-hydroxy-6-methyl-2-(4-phenoxybenzyl)pyrimidin-4-yl)carbonyl}amino)acetate (0.079 g, The title compound (0.065 g, 0.17 mmol. Mp 81-82 °C ; 1H-NMR (400MHz, CD30D) δ : 7.32-7.29 (4Η, m), 7.06 (1H, t, J = 4 Hz), 6.93 (2H, d, J = 8 Hz), 6.89 (2H, d, J = 8

Hz), 4.15 (2H, s), 4.13 (2H, s), 2.48 (3H, s). Example 28 ({[2-(4-Benzylbenzyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

(1) 2-(4-Benzylphenyl)ethylimidoamine acetate NH NH,

The title compound (6.0 g, 21 mmol), m. -131 - 200948788 1H-NMR (400MHz, CD30D) δ : 7.25-7.15 (9H, m), 3.96 (2H, s), 3.73 (2H, s), 1.89 (3H, s). (2) ({[2-(4-Benzylbenzyl)-5-(benzyloxy)-6-methylpyrimidin-4-yl]carbonyl}amine) ethyl acetate

Reference Example 1-(3), Reference Example 5-(2), Reference Example 2-(4), using 2-(4-benzylphenyl)ethyliminoamine acetate (6.0 g, 21 mmol) The title compound (0.34 g, 0.66 mmol) (yield: 36%). 1H-NMR (500MHz, CDC13) &lt;5: 8.32 (1H, t, J = 4 Hz), 7.47 (2H, d, J = 8 Hz), 7.38-7.32 (4H, m), 7.29-7.26 (3H , m), 7.20-7.18 (3H, m), 7.14 (2H, d, J = 8 Hz), 5.08 (2H, s), 4.25 (2H, q, J = 8 Hz), 4.20 (2H, s) , 4.20 (2H, s), 3.95 (2H, s), 2.44 (3H, s), 1.31 (3H, t, J = 8 Hz). (3) ({ [2-(4-Benzylbenzyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino) Ethyl acetate imitation Example 1-(3), {[2-(4-Benzylbenzyl)-5-(benzyloxy)-6-methylpyrimidin-4-yl]carbonylindolyl)acetate (0.34 g, 0.66 mmol) (0.24 g, 0.57 mmol) (yield 87%). 1H-NMR (500MHz, CDC13) &lt;5 : 1 1.35 (1H, s), 8.44 (1H, t, J = 4 Hz), 7.28-7.24 (4H, m), 7.20-7.17 (3H, m), 7.11 (2H, d, J = 4 Hz), 4.27 (2H, q, J = 8 Hz), 4.18 (2H, d, J = 4 Hz), -132- 200948788 4.14 (2H, s), 3.94 (2H , s), 2.51 (3H, s), 1.32 (3H, t, J = 8 Hz). (4) (丨[2-(4-benzylbenzyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid imitation Example 1-(4), using ({[ Ethyl 2-(4-benzylbenzyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonylindolyl)acetate (0.24 g, 0.57 mmol ) White solid (yield 98%). Mp 149-151 °C ;

1H-NMR (400MHz, CD30D)5: 7.24-7.20 (4H, m), 7.15- 7.13 (3H, m), 7.10 (2H, d, J = 8 Hz), 4.13 (2H, s), 4.11 (2H , s), 3.90 (2H, s), 2.46 (3H, s) » Example 29 [({2-[(2-Fluorobiphenyl-4-yl)methyl]-5-hydroxy-6-methyl Pyrimidin-4-yl}carbonyl)amino]acetic acid

❹ (1) 2-fluoro-4-methylbiphenyl 1-bromo-2-fluoro-4-methylbenzene (9.5 g, 50 mmol), phenylboronic acid (7.3 g, 60 mmol), hydrazine (three Phenylphosphine)palladium (5.8 g, 5.0 mmol), tripotassium phosphate hydrate (27 g, 100 mmol) was dissolved in i,2-dimethoxyethane (1 mL) and heated to reflux under a nitrogen atmosphere. hour. After the reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Bi〇tage-133-200948788, solvent: hexane/ethyl acetate), and corresponding to Rf 値 = 0.50 (hexane) of thin layer chromatography. The residue was evaporated to dryness crystal crystal crystal crystal crystal crystal 1H-NMR (400MHz, CDC13) &lt;5: 7.54-7.53 (2H, m), 7.45- 7.42 (2H, m), 7.36-7.31 (2H, m), 7.02 (1H, d, J = 8 Hz) , 6.98 (1H, d, J = 8 Hz), 2.39 (3H, s). (2) 4-(bromomethyl)-2-fluorobiphenyl

The title compound (10.0 g, 38 mmol) (yield: 83%). 1H-NMR (500MHz, CDC13) &lt;5: 7.55-7.53 (2H, m), 7.48- 7.37 (4H, m), 7.25-7.20 (2H, m), 4_51 (2H, s). (3) (2-fluorobiphenyl-4-yl)acetonitrile

Example 13-(5), 4-(bromomethyl)-2-fluorobiphenyl (1.3 g, 5.0 mmol) 1H-NMR (500MHz, CDC13) 5 : 7.55-7.53 (2H, m), 7.47- 7.44 (3H, m), 7.40-7.38 (1H, m), 7.20 (1H, d, J = 8 Hz), 7.16 (1H, d, J = 8 Hz), 3.80 (2H, s). (4) 2-(2-Fluorobiphenyl-4-yl)ethylimidoamine acetate

This title compound (2.0 g, 6.9 mmol) %). 1H-NMR (400MHz, CD30D) ^ : 7.54-7.51 (3H, m), 7.46- 7.43 (2H, m), 7.40-7.36 (1H, m), 7.28-7.23 (2H, m), 3.31 (2H, s), 1.89 (3H, s). (5) [({5-(Benzyloxy)-2-[(2-fluorobiphenyl-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

Reference Example 1-(3), Reference Example 5-(2), Reference Example 2-(4), 2-(2-Fluorobiphenyl-4-yl)ethyliminoamine acetate (2.0 g) The title compound (0.11 g, 0.22 mmol) (yield 12%). 1H-NMR (500MHz, CDC13) &lt;5: 8.32 (1H, t, J = 4 Hz), 7.55-7.54 (2H, m), 7.48-7.47 (2H, m), 7.45-7.33 (7H, m) , 7.19 (1H, d, J = 8 Hz), 7.16 (1H, d, J = 8 Hz), 5.11 (2H, s), 4.27 (2H, s), 4.26 (2H, q, J = 8 Hz) , 4.22 (2H, d, J = 4 Hz), O 2.47 (3H, s), 1.31 (3H, t, J = 8 Hz). (6) [({2-[(2-Fluorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

Example 1-(3), using [({5-(benzyloxy)-2-[(2-fluorobiphenyl-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl) Ethyl acetate ethyl acetate (0.11 g, 0.22 mmol). -135- 200948788 1H.NMR (400MHz, CDC13) &lt;5 : 1 1.42 (1H, s), 8.45 (1H, t, J = 4 Hz), 7.55 -7.52 (2H, m), 7.44-7.41 (2H , m), 7.38-7.34 (2H, m), 7.18 (1H, d, J = 8 Hz), 7.13 (1H, d, J = 8 Hz), 4.28 (2H, q, J = 8 Hz), 4.21 (2H, s), 4.20 (2H, d, J = 4 Hz), 2.54 (3H, s), 1.32 (3H, t, J = 8 Hz). (7) [({2-[(2-Fluorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid imitation Example 1-( 4), using [({2-[(2-fluorobiphenyl-4-yl)methyl)-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.078 g) The title compound (0.062 g, 0.16 mmol. Mp 164-165 °C ; 1H-NMR (400MHz, CD30D) 5 : 7.50-7.48 (2H, m), 7.42- 7.31 (4H, m), 7.20 (1H, d, J = 8 Hz), 7.17 (1H , d, J = 8 Hz), 4.22 (2H, s), 4.14 (2H, s), 2.50 (3H, s). Example 30 {[(5-Hydroxy-6-methyl-2-{[2'-(trifluoromethyl)biphenyl-4-yl]methyl}pyrimidin-4-yl)carbonyl]amino}acetic acid

(1) {[(5-Hydroxy-6-methyl-2-{[2'-(trifluoromethyl)biphenyl-4-yl]methyl}glyridin-4-yl)carbonyl]amino} Ethyl acetate

Example 6_(1), Example 1-(3), obtained by Reference Example 3 (([5-(-136-200948788 benzyloxy)-6-methyl-2-(4-{[( Trifluoromethyl)sulfonyl]oxy}benzyl)pyrimidin-4-yl]carbonyl}amino)acetate (〇_30 g, 0.53 mmol) and [2-(trifluoromethyl)phenyl The title compound (5 g, 0-32 mmol) was obtained (yield: 69%).

lH-NMR (500MHz, CDC13) δ : 11.38 (1Η, s), 8.41 (1H, t, J

G = 5 Hz), 7.74-7.73 (1H, m), 7.56-7.53 (1H, m), 7.47-7.44 (1H, m), 7.36-7.32 (3H, m), 7.27-7.25 (2H, m) , 4.27 (2H, q, J = 8 Hz), 4.26 (2H, s), 4.19 (2H, d, J = 5 Hz), 2.55 (3H, s), 1.32 (3H, t, J = 8 Hz) . (2) {[(5-Hydroxy-6-methyl-2-{[2,-(trifluoromethyl)biphenyl-4-yl]methyl}pyrimidin-4-yl)carbonyl]amino}acetic acid Example 1-(4), using {[(5-hydroxy-6-methyl-2-{[2'-(trifluoromethyl)biphenyl-4-yl]methyl}pyrimidin-4-yl) &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&&&&&&&& NMR (500MHz, DMSO-d6) &lt;5: 12.90 (1H, s), 11.98 (1H, s), 9.49 (1H, t, J = 6 Hz), 7.81 (1H, d, J = 8 Hz), 7.70 (1H, dd, J = 8 Hz, 7 Hz), 7.59 (1H, dd, J = 8 Hz, 7 Hz), 7.38 (2H, d, J = 8 Hz), 7.38 (1H, d, J = 8 Hz), 7.24 (2H, d, J = 8 Hz), 4.22 (2H, s), 4.01 (2H, d, J = 6 Hz), 2.44 (3H, s). Example 3 1 {[(5 -hydroxy-6-methyl-2-{[4'-(trifluoromethyl)biphenyl-4-yl]methyl}pyrimidine-137-200948788 4-yl)carbonyl]amino}acetic acid

(1) {[(5-Hydroxy-6-methyl-2-{[4'-(trifluoromethyl)biphenyl-4-yl]methyl}pyrimidin-4-yl)carbonyl]amino}acetic acid Ethyl ester

Example 6-(1) 'Example 1-(3), obtained with Reference Example 3 ({[5-(benzyloxy)-6-methyl-2-(4-{[(trifluoromethyl)) Ethylsulfonyl]oxyindole benzyl)pyrimidin-4-yl]carbonyl}amino)acetate (0.30 g, 0.53 mmol) and [4-(trifluoromethyl)phenyl]boronic acid (0.20 g) The title compound (0.12 g, 0.25 mmol).

lH-NMR (500MHz, CDC13) &lt;5: 11.39 (1H, s), 8.45 (1H, t, J

=6 Hz), 7.67 (4H, s), 7.54 (2H, d, J = 8 Hz), 7.44 (2H, d, J

=8 Hz), 4.28 (2H, q, J = 7 Hz), 4.24 (2H, s), 4.19 (2H, d, J = 6 Hz), 2·53 (3H, s), 1.32 (3H, t , J = 7 Hz). (2) { [(5-Hydroxy-6-methyl-2-{[4,-(trifluoromethyl)biphenyl-4-yl]methyl}pyrimidin-4-yl)carbonyl]amino}acetic acid Example 1-(4), using {[(5-hydroxy-6-methyl-2-indole[4'-(trifluoromethyl)biphenyl-4-yl]methyl}pyrimidin-4-yl Ethyl acetate (0.12 g, 0.25 mmol) EtOAc (m. MS m/z : 446 (M + H) + ; -138 - 200948788 lH-NMR (500MHz, DMSO-d6) 5 : 12.90 (1H, s), 11.97 (1H, s), 9.49 (1H, t, J = 6 Hz), 7.86 (2H, d, J = 8 Hz), 7.80 (2H, d, J = 8 Hz), 7.67 (2H, d, J = 8 Hz), 7.45 (2H, d, J = 8 Hz), 4-21 (2H, s), 4.01 (2H, d, J = 6 Hz), 2.43 (3H, s). Example 32 ({[2-(3-Biphenyl-4-ylpropyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid

(1) (4-biphenyl-4-yl)butyronitrile

Example 13-(5), 4-(3-bromopropyl)biphenyl (0.28 g, 1.0 mmol) 1H-NMR (400MHz, CDC13) 5 : 7.59-7.54 (4H, m), 7.46- 7.42 (2H, m), 7.36-7.33 (1H, m), 7.27-7.26 (2H, m), 2.83 G (2H , t, J : 8 Hz), 2.36 (2H, t, J = 8 Hz), 2.03 (2H, m). (2) (4-biphenyl-4-yl)butane decylamine acetate

The title compound (2.8 g, 9.4 mmol) m. 1H-NMR (400MHz, CD30D) 5 : 7.59-7.55 (4H, m), 7.43- 7.40 (2H, m), 7.33-7.27 (3H, m), 2.76 (2H, t, J = 8 Hz), 2.49 (2H, t, J = 8 Hz), 2.05 (2H, dd, J = 8 Hz, 8 Hz), 1.89 -139- 200948788 (3H, s). (3) ({[5-(Benzyloxy)-2-(3-biphenyl-4-ylpropyl)-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidine-4- Ethyl acetate

Reference Example M3), Reference Example 5-(2), (4-Biphenyl-4-yl)butaneimideamine acetate (2.8 g, 9.4 mmol) Mmmol) (yield 8.8%). 1H-NMR (500MHz, CDC13) &lt;5: 8.13 (1H, t, J = 4 Hz), 7.59-7.57 (2H, m), 7.52-7.51 (2H, m), 7.48-7.47 (2H, m) , 7.44-7.41 (2H, m), 7.38-7.31 (4H, m), 7.29-7.25 (2H, m), 5.20 (2H, s), 4.27 (2H, q, J = 8 Hz), 4.22 (2H , d, J = 4 Hz), 3.01 (2H, t, J = 8 Hz), 2.74 (2H, t, J = 8 Hz), 2.21 (2H, dd, J = 8 Hz, 8 Hz), 1· 32 (3H,t, J = 8 Hz) o (4)({ [5-(Benzyloxy)-2-(3-biphenyl-4-ylpropyl)-6-methylpyrimidin-4-yl) Carbonyl}amino)ethyl acetate

Referring to Example 2-(4), using ({[5-(benzyloxy)-2-(3-biphenyl-4-ylpropyl)-6-{[(trifluoromethyl)sulfonyl] Ethyloxy}pyrimidin-4-yl]carbonyl}amino)acetate (0.15 g, 0.23 mmol) 1H-NMR (500MHz, CDC13) (5

8-36 (1H, t, J 4 Hz), 200948788 7.59-7.57 (2H, m), 7.52-7.51 (2H, m), 7.47-7.46 (2H, m), 7.44-7.41 (2H, m), 7.39-7.31 (4H, m), 7.30-7.28 (2H, m), 5.09 (2H, s), 4.26 (2H, q, J = 8 Hz), 4.23 (2H, d, J = 8 Hz), 2.99 (2H, t, J = 8 Hz), 2.76 (2H, t, J = 8 Hz), 2.44 (3H, s), 2.20 (2H, dd, J = 8 Hz, 8 Hz), 1.31 (3H, t , J = 8 Hz). (5) ({[2-(3-Biphenyl-4-ylpropyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)ethyl acetate

Example 1-(3), using ({[5-(benzyloxy)-2-(3-biphenyl-4-ylpropyl)-6-methylpyrimidin-4-yl]carbonyl}amino) The title compound (0.071 g, 0.16 mmol) (yield 86%). 1H-NMR (500MHz, CDC13) 5 : 11.34 (1H, s), 8.49 (1H, t,

J = 4 Hz), 7.57 (2H, d, J = 8 Hz), 7.52 (2H, d, J = 4 Hz), 7.43 (2H, t, J = 8 Hz), 7.33 (1H, t, J = 8 Hz), 7.27 (2H, t, J = 8 Hz), 4.27 (2H, q, J = 8 Hz), 4.20 (2H, d, J = 4 Hz), 2.93 (2H, t, J = 8 Hz) ), 2.75 (2H, t, J = 8 Hz), 2.52 (3H, s), 2.16 (2H, dd, J = 8 Hz, 8 Hz), 1.32 (3H, t, J = 8 Hz). (6) ({[2-(3-biphenyl-4-ylpropyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid imitation Example 1-(4), Ethyl ({[2-(3-biphenyl-4-ylpropyl)-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl}amino)acetate (0.071 g, 0.16 mmol) The title compound (0.064 g, 0.16 mmol) Mp 1 84- 1 85 °C ; -141- 200948788 1H-NMR (400MHz, CD30D) δ : 7.57 (2H, d, J = 8 Hz), 7.49 (2H, d, J = 4 Hz), 7.40 (2H , t, J = 8 Hz), 7.29 (1H, t, J = 8 Hz), 7.25 (2H, d, J = 4 Hz), 4.13 (2H, s), 2.90 (2H, t, J =8 Hz) ), 2.73 (2H, t, J = 8 Hz), 2.46 (3H, s), 2.18 (2H, dd, J = 8 Hz, 8 Hz). Example 33 ({[2-(4-Benzylbenzyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonylguanidino)acetic acid

(1) ({[2-(4-Benzylbenzyl)-5-(benzyloxy)-6-methylpyrimidin-4-yl]carbonylguanidinyl) ethyl acetate

Reference Example 4-(6) ({[5-(Benzyloxy)-2-(4-[(t-butoxycarbonyl)(phenyl)amino]benzyl) 6-methylpyrimidine-4 Ethyl-carbonyl]amino)acetate (0.14 g, 0.22 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) The organic layer was extracted with dichloromethane, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (BioUge, solvent: hexane/ethyl acetate). The title compound (0.067 g, 0.13 mmol) (yield: 59%) was obtained from EtOAc (EtOAc) 1H-NMR (500MHz, CDC13) 5 : 8.35 (1H, t, J = 4 Hz), 7.48 -142- 200948788 (2H, d, J = 8 Hz), 7.39-7.33 (3H, m), 7.28-7.23 (4H, m), 7.05-7.03 (3H, m), 6.90 (1H, t, J = 8 Hz), 5.68 (2H, s), 5.09 (2H, s), 4.26 (2H, q, J = 8 Hz), 4.21 (2H, d, J = 4 Hz), 4.18 (2H, s), 2.45 (3H, s), 1.31 (3H, t, J = 8 Hz) 〇(2) ({ [2-( 4-aniline benzyl)-5-hydroxy-6-methylpyrimidine 4-yl] carbonyl} amino) acetate

Example M3), using ({[2-(4-phenylaminobenzyl)-5.(benzyloxy)-6-methylpyrimidin-4-yl)carbonyl}amino)acetate (0.067 g, 0.13 The title compound (0.055 g, 0.13 mmol) (yield: 99%). 1H-NMR (500MHz, CDC13)5: 11.36 (1H, s), 8.47 (1H, t, J = 4 Hz), 7.26-7.23 (5H, m), 7.04-7.01 (3H, m), 6.90 (1H , t, J = 8 Hz), 5.66 (2H, s), 4.27 (2H, q, J = 8 Hz), 4.19 (2H, d, J = 4 Hz), 4.13 (2H, s), 2.52 (3H , s), 1.32 (3H, t, J = 8 Hz). (3) ({[2-(4-Benzylbenzyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid imitation Example 1-(4), using ({[2 Ethyl-(4-anilinobenzyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0·07 8 g, 0.19 mmol) Methyl) white solid (yield 88%). Mp 85-86 °C ; 1H-NMR (400MHz, CD30D) &lt;5 : 7.18-7.16 (4H, m), 7.03-6.99 (4H, m), 6.79 (1H, t, J = 8 Hz), 4.14 (2H, s), 4.10 (2H, 200948788 s), 2.49 (3H, s). Example 34 [({5-Hydroxy-6-methyl-2-[4-(2-phenylethyl)benzyl]pyrimidin-4-yl}carbonyl)amine]acetic acid

(1) [({5-(Benzyloxy)·6-methyl-2-[4-(phenylethynyl)benzyl]pyrimidin-4-yl}carbonyl)amino]acetate

({[5-(Benzyloxy)-6-methyl-2-(4-{[(trifluoromethyl)sulfonyl)oxy}benzyl)pyrimidin-4-yl) obtained in Reference Example 3. Acetyl}amino)acetate (0.57 g, 1.0 mmol), acetylene benzene (0.17 mL, 1.5 mmol), hydrazine (triphenylene) pin (0.12 g, 0.10 mmol), copper iodide (0.038 g, 0.20) Methyl) was dissolved in hydrazine, hydrazine-dimethylformamide (1 mL) and triethylamine (5 mL) and stirred at 50 ° C for 20 hours. After the organic layer was washed with a saturated aqueous solution of ammonium chloride, the organic layer was dried over sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (Biotage, elution solvent: hexane/ethyl acetate), and Rf 値 = 0.40 (hexane/ethyl acetate = 2 The title compound (0.18 g, 0.34 mmol) (yield: 34%). 1H-NMR (400MHz, CDC13) &lt;5: 8.31 (1H, t, J = 4 Hz), 7.53-7.47 (6H, m), 7.39-7.34 (8H, m), 5.10 (2H, s), 4.26 -144- 200948788 (2H, q, J = 8 Hz), 4.25 (2H, s), 4.21 (2H, d, J = 4 Hz), 2.45 (3H, s), 1.32 (3H, t, J = 8 Hz). (2) [({5-Hydroxy-6-methyl-2-[4-(2-phenylethyl)benzyl]pyrimidin-4-yl}carbonyl)amino]ethyl acetate

〇

Example 1-(3), using [({5-(benzyloxy)-6-methyl-2-[4-(phenylethynyl)benzyl]pyrimidin-4-yl}carbonyl)amino] The title compound (0.11 g, 0.26 mmol) (yield: 77%). 1H-NMR (400MHz, COC13) δ : 11.36 (1Η, s), 8.46 (1H, t, J = 4 Hz), 7.30-7.13 (9H, m), 4.28 (2H, q, J = 8 Hz), 4.19 (2H, d, J = 4 Hz), 4.16 (2H, s), 2.90 (4H, s), 2.52 (3H, s), 1.33 (3H, t, J = 8 Hz). (3) [({5-Hydroxy-6-methyl-2-[4-(2-phenylethyl)benzyl]pyrimidin-4-yl}carbonyl)amino]acetic acid imitation Example 1-(4) With [({5-hydroxy-6-methyl-2-[4-(2-phenylethyl)benzyl]pyrimidin-4-yl}carbonyl)amino]acetate (O.ll g, 0.26 The title compound (0.10 g, 0.25 mmol) Mp 149- 1 50 °C ; 1H-NMR (400MHz, CD30D) 5 : 7.23-7.07 (9H, m), 4.13 (2H, s), 4.12 (2H, s), 2.85 (4H, s), 2· 47 (3H, s). Example 35 ({[5-Hydroxy-6-methyl-2-(1,Γ: 4', Γ-biphenyl-4-ylmethyl)pyrimidin-4-yl]carbonyl}amino)acetic acid -145- 200948788 〇Πί^ΟΗ (1)({[5-Hydroxy-6-methyl-2-(1,Γ: 4' ,1"-bitriphenyl-4-ylmethyl)pyrimidine·4 -yl]carbonyl]amino)ethyl acetate

Example 6-(1), Example 1-(3), obtained with Reference Example 3 ({[5-(benzyloxy)-6-methyl-2-(4-{[(trifluoromethyl)) Ethyl sulfonyl]oxy}benzyl)pyrimidin-4-yl]carbonyl}amino)acetate (0.30 g, 0.53 mmol) and 4-biphenylboronic acid (0.21 g, 1.1 mmol) Compound (0. g, 0.23 mmol) solid (yield 43%).

lH-NMR (500MHz, CDC13) &lt;5: 11.39 (1H, s), 8.47 (1H, t, J = 6 Hz), 7.66-7.63 (6H, m), 7.60-7.58 (2H, m), 7.48 -7.42 (4H, m), 7.38-7.35 (1H, m), 4.28 (2H, q, J = 7 Hz), 4.24 (2H, s), 4.20 (2H,d, J = 6 Hz), 2, 55 (3H, s), 1.33 (3H, t, J = 7 Hz). (2) ({[5-Hydroxy-6-methyl-2-(1,Γ: 4', Γ-biphenyl-4-ylmethyl)pyrimidin-4-yl]carbonyl}amino)acetic acid) Example 1-(4), using ({[5-hydroxy-6-methyl-2-(1,Γ: 4',1"-triphenyl-4-ylmethyl)pyrimidine-4- Ethyl acetate (0.11 g, 0.23 mmol) EtOAc (m.j. H)+; -146- 200948788 lH-NMR (500MHz, DMSO-d6) &lt;5: 9.46 (1H, t, J = 6 Hz), 7.78-7.70 (6H, m), 7.67-7.64 (2H, m ), 7.50-7.47 (2H, m), 7.44-7.35 (3H, m), 4.21 (2H, s), 4.00 (2H, q, J = 6 Hz), 2.44 (3H, s) » Example 36 [ ({2-[(4,-Ethylbiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

Ο 丫(1)[({2-[(4,-Ethylbiphenyl-4-yl)methyl]-5-(henyloxy)-6-methylpyridin-4-yl}carbonyl) Amino]ethyl acetate

Example 6-(1), obtained by reference Example 3 (丨[5-(hydroxyl)-6-methyl-2-(4-{[(trifluoromethyl)sulfonyl)oxy} Benzyl)pyrimidinyl]mineyl}amino)acetate (0.30 g, 0.53 mmol) and EtOAc (EtOAc: EtOAc: EtOAc: • 26 mmol) white solid (yield 49%). MS m/z: 53 8 (M + H) +. (2) [({2-[(4,-Ethylbiphenyl-4-yl)methyl) 5-hydroxymethylpyran-4-yl}carbonyl)amino]ethyl acetate

200948788 [({2-[ (4'-Ethylbiphenyl-4-yl)methyl]-5-(benzyloxy)-6-methyl)

Ethyl pyrimidin-4-yl}carbonyl)amino]acetate (0.14 g, 0.26 mmol) was dissolved in ethyl acetate (15 mL), 5% palladium-activated carbon (0.020 g). Stir at room temperature for 1.5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue obtained was dissolved in acetone (10 mL), and the mixture was stirred at room temperature to give a brown color of the reaction mixture. After the reaction mixture was added with isopropyl alcohol to a pale green color, water was added and the organic matter was extracted with ethyl acetate. After the organic layer was concentrated under reduced pressure, the residue obtained was purified by silica gel chromatography (yield: EtOAc/ethyl acetate), and Rf 値 = 0.80 (hexane/ethyl acetate) The title compound (0.030 g, 0.067 mmol) was obtained (yield: 26%). lH-NMR (500MHz, CDC13) (5: 11.39 (1H, s), 8.45 (1H, t, J = 6 Hz), 8.01 (2H, d, J = 8 Hz), 7.67 (2H, d, J = 8 Hz), 7.56 (2H, d, J = 8 Hz), 7.44 (2H, d, J = 8 Hz), 4.28 (2H, q, J = 7

Hz), 4.24 (2H, s), 4.19 (2H, d, J = 6 Hz), 2.63 (3H, s), 2.53 (3H, s), 1.32 (3H, t,; i = 7 Hz). (3) [({2-[(4'-Ethylbiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid imitation example 1-(4) with [({2-[(4,-Ethylbiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino] Ethyl acetate (0.030 g, 0.067 mmol). lH-NMR (500MHz, DMSO-d6) 5 : 11.97 (1H, s), 9.47 (1H, -148- 200948788 t, J = 6 Hz), 8.02 (2H, d, J = 8 Hz), 7.80 (2H , d, J = 8 Hz), 7.68 (2H, d, J = 8 Hz), 7.45 (2H, d, J = 8 Hz), 4.21 (2H, s), 4.00 (2H, d, J = 6 Hz ), 2.60 (3H, s), 2.43 (3H, s). Example 37 [({5-Pentyl-6-methyl-2-[(4-phenylcyclohex-1-yl-1-yl)methyl]-glycol-4-yl}carbonyl)amino] Acetic acid

〇 (1) Methyl 4-phenylcyclohex-1-ene-1-carboxylate

4- Dissolve 4-phenylcyclohexanone (5.0 g, 29 mmol) in dichloromethane (100 mL) and add 2,6-di-tert-butyl-4-methylpyridine (8.8 g, 41 mmol) After that, trifluoromethanesulfonic anhydride (6.3 mL, 38 mmol) was added dropwise at 0 ° C and stirred for 2 hours. After the reaction mixture was concentrated under reduced pressure, the residue was evaporated to ethyl ether. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (yield: hexane/ethyl acetate), and Rf 値 = 0.58 (hexane/ethyl acetate = 5/1) The corresponding fraction was concentrated under reduced pressure to give 4-phenylcyclohex-1-yl trifluoromethanesulfonate (7.6 g, 25 mmol) as a yellow oil (yield 86%). 4-Phenylcyclohex-1-yl trifluoromethanesulfonate (7.6 g, 25 mmol), palladium acetate (0.28 g, 1.3 mmol), triphenylphosphine (〇_65 g, 0.25 mmol), triethyl The amine (0.69 mL, 50 mmol) was dissolved in methanol (2 mL) and a mixture of hydrazine and dimethyl-dimethylformamide (40 mL). 200948788 hours. Water was poured into the reaction mixture, and the organic matter was extracted with diethyl ether. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (Sentech, solvent: hexane/ethyl acetate), and Rf 値=〇·5〇 (hexane/acetic acid) with thin layer chromatography. Ethyl ester = 5/1) EtOAc (EtOAc) lH-NMR (400MHz, CDC13) (5: 7.32 (2H, t, J = 8 Hz), 7.23- 7.21 (3H, m), 7.08 (1H, d, J = 4 Hz), 3.76 (3H, s) , 2.83-2.77 (1H, m), 2.53 (2H, dd, J = 16 Hz, 4 Hz), 2.39-2.28 (2H, m), 2.05-2.02 (1H, m), 1.76 (1H, ddd, J = 12 Hz, 11 Hz, 5 Hz) (2) (4-Phenylcyclohex-1-en-1-yl)methanol

Example 13-(3) 'Methyl 4-phenylcyclohex-1-ene-1-carboxylate (3.7 g, 17 mmol) Yield 82%) 〇lH-NMR (400MHz, CDC13) 5 : 7.32 (2H, t, J = 8 Hz), 7.24- 7.19 (3H, m), 5·79 (1H, d, J = 4 Hz) , 4.07 (2H, s), 2.82-2.76 (1H, m), 2.35 (1H, d, J = 16 Hz), 2.24-2.16 (3H, m), 2.01 (1H, d, J = 16 Hz), 1.79 (1H,ddd,J = 13 Hz, 11 Hz, 6 Hz) o (3) [4-(Bromomethyl)cyclohex-3-ene-i-yl]benzene

The title compound (3.5 g, 14 mmol) was obtained from m. Amorphous solid (quantitative yield). 1 H-NMR (400 MHz, CDC 13) &lt; 5 : 7.31 (2H, t, J = 7 Hz), 7.23 - 7.19 (3H, m), 5.98 (1H, s), 4.00 (2H, s), 2.81- 2.75 (1H, m), 2.3 8-2.27 (3H, m), 2.21 (1H, d, J = 12 Hz), 2.04-2.01 (1H, m), 1.81 (1H, ddd, J = 12 Hz, 11 Hz, 6 Hz). (4) (4-Phenylcyclohex-buten-1-yl)acetonitrile

Example 13-(5), [4-(bromomethyl)cyclohex-3-en-1-yl]benzene (3.5 g, 14 mmol) Material (yield 62%). lH-NMR (400MHz, CDC13) (5: 7.32 (2H, t, J = 8 Hz), 7.23-

7.19 (3H, m), 5.89 (1H, s), 3.06 (2H, s), 2.80-2.76 ( 1H, m), 2.37 (1H, d, J = 16 Hz), 2.25-2.17 (2H, m) , 2.13 (1H, d, J = 16 Hz), 2.04-2.01 (1H, m), 1.82 (1H, ddd, J = 12 Hz, 11 Hz, 5 Hz). (5) 2-(4-Phenylcyclohex-1-en-1-yl)ethylenimineamine hydrochloride

Reference Example 1-(1), (2), (4-phenylcyclohex-1-en-1-yl)acetonitrile (1.6 g, 8.7 mmol) Solid (yield 78%). lH-NMR (400MHz, CDC13) &lt;5: 7.31-7.17 (5H, m), 5.89 (1H, -151- 200948788 s), 3.36 (2H, s), 2.74 (1H, m), 2.35 (1H, d, J = 16 Hz), 2.21-2.19 (2H, m), 2.09-2.05 (1H, m), 1.93 (1H, m), 1.77-1.75 (1H, m). (6) 5-(Benzyloxy)-6-hydroxy-2-[(4-phenylcyclohex-1-en-1-yl)methyl]pyrimidine-4-carboxylic acid tert-butyl ester

Reference Example 1-(3), 2-(4-Phenylcyclohex-1-en-1-yl)ethylenimineamine hydrochloride (1.7 g, 6.8 mmol) 6.8 mmol) white solid (quantitative yield). MS m/z : 473 (M + H) + ; lH-NMR (400MHz, CDC13) 5 : 7.43-7.34 (5H, m), 7.31-7.26 (2H, m), 7.23-7.17 (3H, m), 5.46 (1H, s), 5.02 (2H, s), 3.64 (2H, s), 2.78 (1H, t, J = 12 Hz), 2.33-2.14 (4H, m), 1.96 (1H,d, J = 13 Hz), 1.84- 1.7 5 ( 1 H, m), 1.59 (9H, s). (7) 5-(Benzyloxy)-6-methyl-2-[(4-phenylcyclohex-buten-1-yl)methyl]pyridin-4-carboxylic acid tert-butyl ester

Reference Example 2-(3), Reference Example 2-(4), 5-(Benzyloxy)-6-hydroxy-2-[(4-cyclohex-1-en-1-yl)methyl] Pyrimidine-4-carboxylic acid tert-butyl ester (3.2 g, 6.8 mmol) gave the title compound (j. -152- 200948788 MS m/z : 471 (M + H)+ ; lH-NMR (400MHz, CDC13) 5 : 7.43-7.34 (5H, m), 7.31-7.26 (2H, m), 7.23-7.17 (3H , m), 5.46 (1H, s), 5.02 (2H, s), 3.64 (2H, s), 2.78 (1H, t, J = 14 Hz), 2.47 (3H, s), 2.33-2.14 (4H, m), 1.96 (1H, d, J = 14 Hz), 1.83- 1.75 ( 1 H, m), 1.59 (9H, s). (8) [({5-(Benzyloxy)-6-methyl-2-[(4-phenylcyclohex-1-en-1-yl)methyl]pyrimidin-4-yl}carbonyl)amine Ethyl acetate

Example 18-(4), using 5-(benzyloxy)-6-methyl-2-[(4-phenylcyclohex-1-en-1-yl)methyl]pyrimidine-4-carboxylate The title compound (0.85 g, 1.7 mmol) was obtained as a yellow solid (yield: 94%). /1):

MS m/z: 500 (M + H) + ; lH-NMR (400 MHz, CDC13) (5: 8.41 (1H, t, J = 6 Hz), 7.50 (2H, d, J = 8 Hz), 7.40- 7.17 (8H, m), 5.52 (1H, s), 5.13 (2H, s), 4.28 (2H, q, J = 8 Hz), 4.25 (2H, d, J = 6 Hz), 3.62 (2H, s ), 2.83-2.76 ( 1H, m), 2.47 (3H, s), 2.35-2.14 (4H, m), 1.98-1.94 (1H, m), 1.86- 1.75 ( 1H, m), 1.32 (3H, t , J = 7 Hz). (9) [({5-Hydroxy-6-methyl-2-[(4-phenylcyclohex-1-en-1-yl)methyl]pyrimidin-4-ylindole) Carbonyl)amino]ethyl acetate-153- 200948788

Example 26-(1), using [({5-(benzyloxy)-6-methyl-2-[(4-phenylcyclohex-1-en-1-yl)methyl]pyrimidine- Ethyl 4-ethyl}carbonyl)amino]acetate (150 mg, 0.30 mmol) Thin layer chromatography Rf 値 = 0.58 (hexane / ethyl acetate = 2 / 1); MS m / z: 410 (M + H) + ; lH-NMR (400 MHz, CDC13) 5 : 11.37 (1H, s) , 8.52 (1H, t, J 〇=6 Hz), 7.40-7.16 (5H, m), 5.49 (1H, s), 4.29 (2H, q, J = 7

Hz), 4.22 (2H, d, J = 6 Hz), 3.56 (2H, s), 2.82-2.7 5 (1H, m), 2.55 (3H, s), 2.31 (1H, d, J = 16 Hz) , 2.22-2.1 1 (3H, m)5 1.97- 1.92 (1H, m), 1.85- 1.75 ( 1H, m), 1.32 (3H, t, J = 7 Hz) o (10) [({5-hydroxyl -6-methyl-2-[(4-phenylcyclohex-1-en-1-yl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid imitation Example 1-(4), Ethylacetate with [({5-hydroxy-6-methyl-2-[(4-phenylcyclohexanindole-1-yl)methyl]pyrimidin-4-yl}carbonyl)amino]] The title compound (78 mg, 0.20 mmol. m p 1 6 3. . MS m/z : 382 (M + H)+ ; 1H-NMR (400MHz, CDC13) 5 : 11.29 (1H, s), 8.49 (1H, t J = 6 Hz), 7.30-7.16 (5H, m) , 5.49 (1H, s), 4.30 (2H, d, j -154- 200948788 6 Hz), 3.57 (2H, s), 2.78 (1H, t, J = 1 1 Hz), 2.55 (3H, s), 2.34-2.11 (4H, m), 1.97 (1H, d, J = 13 Hz), 1.84- 1.73 (1H, m). Example 3 8 [({2-[(2',4'-Dichlorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-ylindolecarbonyl)amino]acetic acid

仿 Example 6-(1), Example 1-(3), and Example 1-(4), which were obtained by Reference Example 3 ({[5-(benzyloxy)-6-methyl-2-) (4-([(Trifluoromethyl)sulfonyl)oxy}benzyl)pyrimidin-4-yl]carbonyl}amino)acetate (0.30 g, 0.53 mmol) and 2,4-dichlorobenzene The title compound (0.060 g, 0.13 mmol) was obtained as a white solid (yield: 25%) MS m/z: 446 (M + H) + 1H-NMR (500 MHz, DMS 〇- D6) δ 9 · 4 8 (1 H, t, J = 5 Hz), 7.72 (1H, d, J = 2 Hz), 7.50 (1H, dd, J = 8 Hz, 2 Hz), 7.42 (3H, d, J = 8 Hz), 7.36 (2H, d, J = 8 Hz), 4.21 (2H, s), 4.00 (2H, d, J = 5 Hz), 2.44 (3H, s). Example 39 [ ({2-[(4'-T-butylbiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

-155- 200948788 Example 6-(1), Example 1-(3), and Example 1-(4), obtained by reference Example 3 ({[5-(benzyloxy)-6-methyl) 2-(4-{[(Trifluoromethyl)sulfonyl]oxy}benzyl)pyrimidin-4-yl]carbonyl}amino)acetate (〇·3〇g, 0.53 mmol) and 4 -t-Butylphenylboronic acid (0.19 g, 1.1 mmol) EtOAc (md. 500MHz, DMSO-d6) δ 11.95 (1H, s), 9.48 (1H, t, J = 5 Hz), 7.56-7.54 (4H, m), 7.46 (2H, d, J = 8 Hz), 7.39 (2H , d, J = 8 Hz), 4.18 (2H, s), 4.02 (2H, d, J = 5 Hz), 2.43 (3H, s), 1.30 (9H, s). Example 40 [({2-[2-(3-Fluorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

(1) (3-fluorobiphenyl-4-yl)acetonitrile

(4-Bromo-2-fluorophenyl)acetonitrile (6.6 g, 31 mmol) was dissolved in 1,2-dimethoxyethane (60 mL), phenyl boronic acid (4.5 g, 37 mmol) After the (triphenylphosphine)palladium complex (3.6 g, 3.1 mmol) and potassium phosphate hydrate (16 g, 61 mmol), the mixture was refluxed for 17 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, the insoluble matter was filtered. After the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (sssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss The title compound (2.9 g, 14 mmol lH-NMR (500MHz, CDC13) δ: 7.56 (2Η, d, J = 7 Hz), 7.51 (1H, t, J = 9 Hz), 7.47 (2H, t, J = 8 Hz), 7.41 (2H, t, J = 8 Hz), 7.34 (1H, d, J = 9 Hz), 3·81 (2H, s). (2) 2-(3-Fluorobiphenyl-4-yl)ethyliminoamine acetate

The title compound (3.2 g, 11 mmol) m. lH-NMR (500MHz, CD30D) &lt;5: 7.64 (2H, d, J = 8 Hz), 7.5 0 (1H, t, J = 9 Hz), 7.49-7.44 (4H, m), 7.39 (1H, d, J = 7 Hz), 3.91 (2H, s), 1.89 (3H, s).

(3) [{5-(Benzyloxy)-2-[(3-fluorobiphenyl-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

Reference Example 1-(3), Reference Example 1-(4), Reference Example 2-(3), Reference Example 2-(4), 2-(3-Fluorobiphenyl-4-yl)ethylimine The title compound (0.21 g, 0.41 mmol. MS m/z : 514 (M + H) + ; 1H-NMR (500MHz, CDC13) 5 : 8.31 (1H, t, J = 6 Hz), -157- 200948788 7.59 (2H, d, J = 8 Hz) , 7.48 (2H, d, J = 8 Hz), 7.44 (2H, t, J = 7 Hz), 7.40-7.30 (7H, m), 5.11 (2H, s), 4.33 (2H, s) 4.24 (2H , q, J = 8 Hz), 4.19 (2H, d, J = 6 Hz), 2.46 (3H, s), 1.29 (3H, t, J = 8 Hz). (4) [({2-[2-(3-Fluorobiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid imitation Example 1 -(3), Example 1-(4), using [{5-(benzyloxy)-2-[(3-fluorobiphenyl-4-yl)methyl]-6-methylpyrimidine-4- Ethyl acetate (0.21 g, 0.41 mmol)yield MS m/z : 396 (M + H) + ; lH-NMR (500 MHz, CD30D) (5: 7.61 (2H, d, J = 7 Hz), 7.42 (2H, t, J = 7 Hz), 7.39- 7.30 (4H, m), 4.27 (2H, s), 4.11 (2H, s), 2.48 (3H, s). Example 4 1 [({5-hydroxy-6-methyl-2-[4-( 2-Phenyloxy)benzyl]pyrimidin-4-yl}carbonyl)amino]acetic acid

(1) [({5-Hydroxy-6-methyl-2-[4-(2-phenylethoxy)benzyl]pyrimidin-4-yl}carbonyl)amino]ethyl acetate

Reference Example 2-(5) ({ [5-(Benzyloxy)-2-(4-hydroxybenzyl)-6-methylpyrimidine-158- 200948788

Pyridin-4-yl]carbonyl}amino)acetic acid (0.27 g, 0.62 mmol) was dissolved in tetrahydrofuran (10 mL), and tributylphosphine (0.38 g, 1-9 mmol), 2-phenylethanol (0.15 g) After 1.2 mmol) and 1,1·-(azodicarbonyl)dipiperidine (0.31 g, 1.2 mmol), the mixture was stirred for 1 hour at EtOAc and stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (yield: hexane/ethyl acetate), and Rf 値. /1) Concentration under reduced pressure to give [({5-benzyloxy-6-methyl-2-[4-(2-phenylethoxy)benzyl]pyrimidin-4-yl}carbonyl) Ethyl acetate ethyl acetate (0.22 g, 0.41 mmol) (yield: 66%). This was dissolved in ethyl acetate (15 mL), and 5% palladium-activated carbon (0.030 g) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (Sen Technology Co., Ltd., elution solvent: hexane/ethyl acetate), and Rf 値 = 0.50 (hexane/ethyl acetate = 3/1) corresponding to thin layer chromatography. The title compound (0.17 g, 0.40 mmol) MS m/z: 450 (M + H) + ; 1H-NMR (500MHz, CDC13) &lt;5: 11.34 (1H, s), 8.43 (1H, brs), 7.34-7.21 (7H, m), 6.83 ( 2H, d, J = 8 Hz), 4.26 (2H, q, J = 7 Hz), 4.18 (2H, d, J = 5 Hz), 4.14 (2H, t, J = 7 Hz), 4.11 (2H, s), 3.08 (2H, t, J = 7 Hz), 2.51 (3H, s), 1.32 (3H, t, J = 7 Hz). (2) [((5-Hydroxy-6-methyl-2-[4-(2-phenylethoxy)benzyl]pyrimidin-4-yl}carbonyl)amino]acetic acid]-159- 200948788 1-3, using [({5-hydroxy-6-methyl-2-[4-(2-phenylethoxy)benzyl]pyrimidin-4-yl}carbonyl)amino]acetate (0.17 g) , title compound (0.10 g, 0.24 mmol) (yield: 59%). MS m/z: 422 (M + H) + 1H-NMR (500 MHz, DMSO-d6) &lt;5: 11.92 (1H, brs), 9.44 (1H, brs), 7.31-7.18 (5H, m), 7.20 (2H, d, J = 9 Hz), 6.84 (2H, d, J = 9 Hz), 4.13 (2H, t, J = 7 Hz), 4.06 (2H, s), 4.00 (2H, d, J = 5 Hz), 3.00 (2H, t, J = 7 Hz), 2·45 (3H, s). 42 ({[2-(biphenyl-4-ylmethyl)-6-(difluoromethyl)-5-hydroxypyrimidin-4-yl]carbonyl}amino)acetic acid

(1) 5-(Benzyloxy)-2-(biphenyl-4-ylmethyl)-6-methylpyrimidine-4-carboxylic acid tert-butyl ester

Reference Example 2-(3), Reference Example 2-(4), 5-(Benzyloxy)-2-(biphenyl-4-ylmethyl)-6-hydroxyl group obtained by Reference Example 5-(1) Pyrimidine-4-carboxylic acid tert-butyl ester (3.0 g, 6.4 mmol) afforded the title compound (2 g. 1H-NMR (500MHz, CDC13) δ: 7.58-7.30 (1 4Η, m), 4.98 (2H, s), 4.29 (2H, s), 2.45 (3H, s), 1.59 (9H, s). -160- 200948788 (2) 5-(Benzyloxy)-2-(biphenyl-4-ylmethyl)-6-(difluoromethyl)pyrimidine-4-carboxylic acid tert-butyl ester and 5-(() Benzyloxy)-2-(biphenyl-4-ylmethyl)-6-(fluoromethyl)pyrimidine-4-carboxylic acid tert-butyl ester

Dissolve 3-(benzyloxy)-2-(biphenyl-4-ylmethyl)-6-methylpyrimidine-4-carboxylic acid tert-butyl ester (1.7 g, 3.6 mmol) in tetrahydrofuran (50 mL) After adding a solution of lithium hexamethyldiazepine in tetrahydrofuran (1 M, 9.1 mL, 9.1 mmol) at -78 ° C under a nitrogen atmosphere, the mixture was stirred at the same temperature for 30 minutes. After adding N-fluorobenzenesulfonimide (2.9 g, 9.1 mmol) to the reaction solution at -78 ° C, the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was warmed to 10 ° C, and further stirred for 2 hr. After the extract was concentrated under reduced pressure, the residue obtained was purified by silica gel chromatography (Sen technology, solvent: hexane/ethyl acetate) to give 5-(benzyloxy)-2-(biphenyl-4-yl) Methyl)-6-(difluoromethyl)pyrimidine-4-carboxylic acid tert-butyl ester (1.2 g, 2.4 mmol, yield 66%) and 5-(benzyloxy)-2-(biphenyl-4) -Methylmethyl-6-(fluoromethyl)pyrimidine-4-carboxylic acid tert-butyl ester (0.25 g, 0.52 mmol, yield 14%), each as a pale yellow oil. Low polar compound: 5-(benzyloxy)-2-(biphenyl-4-ylmethyl)-6-(difluoromethyl)pyrimidine-4-carboxylic acid tert-butyl ester thin layer chromatography Rf値= 0.70 (hexane/ethyl acetate = 3/1); MS m/z: 503 (M + H)+; Highly polar compound: 5-(benzyloxy)-2-(biphenyl-4-ylmethyl) - 6-(fluoromethyl)pyrimidine-4-carboxylic acid tert-butyl ester-161- 200948788 Thin layer chromatography Rf 値 = 0.65 (hexane / ethyl acetate = 3 / 1); MS m / z : 485 (M + H)+ ;. (3) ({[2_(Biphenyl-4-ylmethyl)-6-(difluoromethyl)-5-hydroxypyrimidin-4-yl]carbonyl}amino)acetic acid

Reference Example 2-(5), Example 1-(3), Example ι_(4), 5-(Benzyloxy)-2-(biphenyl-4-ylmethyl)-6-(di) Fluoromethyl)pyrimidine-4-furic acid tert-butyl ester (0.20 g, 0.40 mmol). MS m/z : 414 (M + H) + ; 1H-NMR (500MHz, CDC13) 5 : 9.73 (1H, brs), 7.64-7.59 (4H, m), 7.46-7.42 (4H, m), 7.34 ( 1H, t, J = 7 Hz), 7.15 (1H, t, J = 53 Hz), 4.30 (2H, s), 4.04 (2H, d, J = 5 Hz). Example 43 ({[2-(Biphenyl-4-ylmethyl)-6-(fluoromethyl)-5-hydroxypyrimidin-4-yl]carbonyl}amino)acetic acid

Reference Example 2-(5), Example 26-(1), Example 1-(4), 5-(Benzyloxy)-2-(biphenyl-4-) obtained by Example 42-(2) The title compound (0.026 g, 0.066 mmol MS m/z : 396 (M + H) + ; -162 - 200948788 1H-NMR (500MHz, CDC13) δ : 9.64 (1H, brs), 7.63-7.58 (4H, m), 7.46-7.40 (4H, m ), 7.34 (1H, t, J = 8 Hz), 5.56 (2H, d, J = 47 Hz), 4.26 (2H, s), 4.03-4.01 (2H, m)-&gt; Example 44 [({ 2-[4-(5-Benzylpyridin-2-yl)benzyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

〇 (1) 5-Bromo-2-[4-(bromomethyl)phenyl]pyridine

5-Bromo-2-(4-methylphenyl)pyrrole (1.6 g, 6.5 mmol), N-bromosuccinate (1.5 g, 8.4 mmol), 2,2'-azobis (iso) The butyronitrile) (〇.i6 g, 0.98 mmol) was dissolved in carbon tetrachloride (65 mL) and heated to reflux for 1 hour. After the reaction solution was cooled to room temperature, the insoluble matter was filtered. After the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (Sen technology, solvent: hexane / ethyl acetate), and Rf 値 = 50 The title compound (2. g, 65 mmol) was obtained as white solid (yield).

lH-NMR (500MHz, CDC13)5: 8.74 (1H, s), 7.95 (2H, d, J = 9 Hz), 7.88 (1H, d, J = 7 Hz), 7.62 (1H, d, J = 9 Hz), 7.5 〇 (2H, d, J = 9 Hz), 4.54 (2H, s). (2) [4-(5-Bromopyridin-2-yl)phenyl]acetonitrile

-163- 200948788 5-Bromo-2·[4-(bromomethyl)phenyl]pyridine (2.1 g, 6.5 mmol), tetrabutylammonium cyanide (2.6 g, 9.8 mmol) dissolved in acetonitrile (100 mL) ), stirring at room temperature for 15.5 hours. After the reaction mixture was concentrated under reduced pressure, the residue obtained was purified by silica gel column chromatography (yield solvent: hexane/ethyl acetate), and Rf 値 = 〇. The title compound (0.59 g, 2.2 mmol) of white solid (yield: 33%).

lH-NMR (5 〇〇 MHz, CDC13) 5 : 8.74 (1H, s), 7.99 (2H, d, J = 8 Hz), 7.89 (1H, d, J = 8 Hz), 7.63 (1H, d, J = 8 Hz), 7.45 (2H, d, J = 9 Hz), 3.82 (2H, s). (3) [4-(5-Benzylpyridin-2-yl)phenyl]acetonitrile

[4-(5-Bromopyridin-2-yl)phenyl]acetonitrile (0.59 g, 2.2 mmol) was dissolved in tetrahydrofuran (20 mL) and 2-benzyl-4,4,5,5-tetramethyl -1,3,2-dioxaborane (0.57 g, 2.6 mmol), [1,1'-bis(diphenylsulfenyl)ferrocene]dichloride

After a palladium-dichloromethane complex (0.18 g, 0.22 mmol) and a carbonic acid (2.1 g, 6.5 mmol), the mixture was heated to reflux for 18 hours under a nitrogen atmosphere. After the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, eluting solvent: hexane/ethyl acetate, and Rf 値 = 0.40 (hexane/ethyl acetate) The title compound (0.42 g, 1.5 mmol) of white solid (yield: 68%). lH-NMR (500MHz, CDC13) (5: 8.58 (1H, s), 7.99 (2H, d, J = 8 Hz), 7.65 (1H, d, J = 8 Hz), 7.54 (1H, d, J = 8 Hz), 7.42 -164- 200948788 (2H, d, J = 9 Hz), 7.36-7.28 (2H, m), 7.26-7.19 (3H, m), 4.03 (2H, s), 3.81 (2H, s (4) 2-[4·(5-Benzylpyridin-2-yl)phenyl]ethyliminoamine acetate

This title compound (0-54 g, 1.5 mmol) (Quantity of yield).

MS m/z: 302 (M + H)+. (5) 5-(Benzyloxy)-2-[4-(5-benzylpyridin-2-yl)benzyl]-6-{[(trifluoromethyl)sulfonyl]oxy}pyrimidine- 4-carboxylic acid tert-butyl ester

Reference Example 1-(3), Reference Example 2-(3), using 2-[4-(5-benzylpyridin-2-yl)phenyl]ethyliminoamine acetate (0.54 g, 1·) The title compound (0.45 g, 0.65 mmol. 1H-NMR (500MHz, CDC13) δ : 8.56 (1Η, s), 7.91 (2H, d, J = 8 Hz), 7.62 (1H, d, J = 8 Hz), 7.51 (1H, d, J = 8 Hz), 7.45 (2H, d, J = 9 Hz), 7.41-7.34 (4H, m), 7.3 3-7.28 (2H, m), 7.25-7.18 (4H, m), 5.11 (2H, s), 4.29 (2H, s), 4.01 (2H, s), 3.81 (2H, s), 1.56 (9H, s). (6) 5-(Benzyloxy)_2-[4-(5-benzylpyridin-2-yl)benzyl]-6-methylpyrimidine-4-carboxylic acid tert-butyl ester -165- 200948788

Referring to Example 2-(4), 5-(benzyloxy)-2-[4-(5-benzylindole/steep 2-yl)benzyl]-6-{[(trifluoromethyl) Sulfhydryl]oxy}pyrimidine_4_residual acid terpene vinegar (0.45 g, 0.65 mmol) gave the title compound (0.28 g, 0.51 1H-NMR (500MHz, CDC13) 5 : 8.55 (1H, s), 7.91 (2H, d, J = 8 Hz), 7.62 (1H, d, J = 8 Hz), 7.50 (1H, d, J = 8 Hz), 7.47 (2H, d, J = 9 Hz), 7.43-7.34 (4H, m), 7.34-7.28 (2H, m), 7.25-7.18 (4H, m), 4.98 (2H, s), 4.30 (2H, s), 4.00 (2H, s), 2.43 (3H, s), 1.56 (9H, s). (7) [({5-(Benzyloxy)-2-[4-(5-benzylpyridin-2-yl)benzyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid Ethyl ester

Reference Example 2-(5), 5-(Benzyloxy)-2-[4-(5-benzylpyridin-2-yl)benzyl]-6-methylpyrimidine-4-carboxylic acid

The title compound (0.29 g, 0.49 mmol)yield (yield: 97%). lH-NMR (500MHz, CDC13) 5 : 8.56 (1H, s), 8.32 (1H, t, J = 6 Hz), 7.92 (2H, d, J = 7 Hz), 7.62 (1H, d, J = 8 Hz), 7.51 (1H, d, J = 8 Hz), 7.48-7.41 (3H, m), 7.40-7.28 (5H, m), 7.25-7.19 (4H, m), 5.09 (2H, s), 4.29 (2H, s), 4.24 (2H, q, J =7 Hz), 4.21 (2H, d, J = 6 Hz), 4.01 (2H, s), 2.45 (3H, s), -166- 200948788 1.30 ( 3H, t, J = 7 Hz). (8) [({2-[4-(5-Benzylpyridin-2-yl)benzyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetate

[({5-(Benzyloxy)2-[4-(5-benzylpyridin-2-yl)benzyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetate ( 0.29 g, 0.49 mmol) was dissolved in dichloromethane (7 mL), EtOAc (3 mL). The organic layer was dried over sodium sulfate, and the residue was concentrated under reduced pressure. The title compound (0.22 g, 0.43 mmol), m. m. NMR (500MHz, CDC13) &lt;5: 11.38 (1H, s), 8.55 (1H, s), 8.43 (1H, t, J = 6 Hz), 7.90 (2H, d, J = 8 Hz), 7.62 ( 1H, d, J =7 Hz), 7.50 (1H, d, J = 6 Hz), 7.42 (2H, d, J = 8 Hz), 7.33-7.19 (5H, m), 4.27 (2H, q, J = 7 Hz), 4.23 (2H, s), 4.19 (2H, d, J = 6 Hz), 4.01 (2H, s), 2.52 (3H, s), 1.31 (3H, t, J =7 Hz). (9) [({2-[4-(5-Benzylpyridin-2-yl)benzyl]-5- Hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid imitation Example 1-(4) with [({2-[4-(5-benzylpyridin-2-yl)benzyl)] -5-Hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.22 g, 0.43 - 167 - 96%) MS m/z : 469 (M + H) + ; lH-NMR (500MHz, DMSO-d6) 5 : 9.28 (1H, brs), 8.56 (1H, s), 7.95 (2H, d, J = 8 Hz), 7.82 (1H, d, J = 7 Hz), 7.68 (1H, d, J = 8 Hz), 7.39 (2H, d, J = 9 Hz), 7.32-7.25 (3H, m), 7.24-7.17 (2H, m), 4.18 (2H, s), 3.99 (2H, s), 3.81 (2H, s), 2.40 (3H, s). Example 45 {[(5-Hydroxy-6-methyl-2-{[4'-(pyridin-3-ylmethyl)biphenyl-4-yl]methyl}pyrimidin-4-yl)carbonyl]amine Acetic acid

(1) 3-(4-Bromobenzyl)pyridine Dissolve copper bromide (2_0 g, 8.6 mmol), butyl nitrite (1.2 mL, 11 mmol) in acetonitrile (60 mL) at 0 ° C After stirring a solution of 4-(pyridin-3-ylmethyl)aniline (1.4 g, 7.3 mmol) in EtOAc (60 mL), After ethyl acetate was added to the reaction mixture, the organic layer was washed with saturated aqueous sodium hydrogen carbonate. After the filtrate was concentrated under reduced pressure, the obtained residue was purified by silica gel chromatography (yield, solvent solvent: hexane/ethyl acetate), and Rf 値 = 0.70 (hexane/ethyl acetate = The title compound (0.95 g, 0.38 mmol) m. -168- 200948788 lH-NMR (500MHz, CDC13) 5 : 8.53-8.45 (2H, m), 7.45-7.39 (1H, m), 7.42 (2H, d, J = 9 Hz), 7.23-7.19 (1H, m), 7.05 (2H,d, J = 9 Hz), 3.93 (2H, s). (2) [4' -(pyridin-3-ylmethyl)biphenyl-4-yl]acetonitrile

a mixed solution of 3-(4-bromobenzyl)pyridine (1.8 g, 7.3 mmol) in tetrahydrofuran (1 mL) and water (7.5 mL), [4-(4,4,5,5- Tetramethyl-1,3,2·dioxaborolan-2-yl)phenyl]acetonitrile (2.2 g, 8.7 mmol), [1,1,-bis(diphenylphosphino)ferrocene] The ruthenium chloride methylene chloride complex (0.59 g, 0.73 mmol) and carbonic acid (7.1 g, 22 mmol) were heated under reflux for 12 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, ethyl acetate was added and washed with water. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (yield: EtOAc/ethyl acetate), and Rf 値 = 0.30 The title compound (1.5 g, 5.4 mmol)yield (yield: 75%). lH-NMR (500MHz, CDC13) 5 : 8.54 (1H, s), 8.48 (1H, d, J = 4 Hz), 7.99 (2H, d, J = 8 Hz), 7.64-7.55 (2H, m), 7.55-7.49 (3H, m), 7.44-7.37 (2H, m), 7.26-7.22 (1H, m), 4.03 (2H, s), 3.79 (2H, s). (3) 2-[4'-(pyridin-3-ylmethyl)biphenyl-4-yl]ethyliminoamine acetate

The title compound (2.0 g, m.j.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 5.4 mmol) white solid (quantitative yield). MS m/z: 302 (M + H) + ;. (4) 5-(Benzyloxy)-2-{[4'-(pyridin-3-ylmethyl)biphenyl-4-yl]methyl b-6- {[(trifluoromethyl)sulfonyl Oxy}pyrimidine-4-carboxylic acid tert-butyl ester

Reference Example 1-(3), Reference Example 2-(3), using [4'-(pyridin-3-ylmethyl)biphenyl-4-yl]ethyliminoamine acetate (2.0 g, 5.4) The title compound (0.67 g, 0.97 mmol. 1H-NMR (500MHz, CDC13) &lt;5: 8.54 (1H, s), 8.48 (1H, d, J = 4 Hz), 7.99 (2H, d, J = 8 Hz), 7.64-7.55 (2H, m ), 7.55-7.49 (3H, m), 7.44-7.37 (5H, m), 7.26-7.15 (3H, m), 5.11 (2H, s), 4.28 (2H, s), 4.02 (2H, s), 1.56 (9H, s). (5) 5-(Benzyloxy)-6-methyl-2-{[4'-(pyridin-3-ylmethyl)biphenyl-4-yl]methyl}pyrimidine-4-carboxylic acid III Butyl ester

Referring to Example 2-(4), 5-(benzyloxy)-2-{[4'-(pyridin-3-ylmethyl)biphenyl-4-yl]methyl}-6-{[( The title compound (0.25 g, 0.45 mmol) of a yellow oily material » 1H-NMR (500MHz, CDC13) 5 : 8.54 (1H, s), 8.48 (1H, d, -170- 200948788 J = 4 Hz), 7.52-7.32 (1 3H, m), 7.26-7.20 (2H, m), 4.98 (2H, s), 4·28 (2H, s), 4_〇l (2H, s), 2.44 (3H, s), 1.57 (9H, s) 〇 (6) {[ (5-Hydroxy-6-methyl-2. {[4,-(pyridin-3-ylmethyl)biphenyl-4-yl]methyl}pyrimidin-4-yl)carbonyl]amino}acetic acid oxime Reference Example 2-(5), Example 44-(8), Example 1-(4) 'Use 5-(benzyloxy)-6-methyl-2-{[4,-(pyridine-3- The title compound (0.12 g, 0.26 mmol) of white solid (yield: 57%). . MS m/z: 469 (M + H).; lH-NMR (500MHz, DMSO-d6) 5 : 9.38 (1H, brs), 8.54 (1H, s), 8.41 (1H, s), 7.66 (1H, d, J = 7 Hz), 7.55 (4H, brs), 7.43-7.34 (2H, m), 7.34-7.28 (3H, m), 4.17 (2H, s), 4.00 (2H, s), 3_91 (2H , s), 2.41 (3H, s). Example 46 {[(5-Hydroxy-6-methyl-2-{[4'-(pyridin-4-ylmethyl)biphenyl-4-yl]methyl}pyrimidin-4-yl)carbonyl]amine Acetic acid

(1) [4-(Pyridin-4-ylmethyl)phenyl]boronic acid pinacol ester

Dissolve 4-(4-bromobenzyl)pyridine (0.70 g, 2.8 mmol) in dioxane (5 mL), and add bis(pinamate) diborane (0.86 g, 3.4) under nitrogen. Ment) '[Ι,Γ-bis(diphenylphosphino)ferrocene]palladium dichloride methylene chloride mis-171- 200948788 compound (0·12 g, 0·14 mmol) and potassium acetate (1. 〇g, i〇mm〇im, stirred at 90 ° C for 3 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The obtained residue was chromatographed on silica gel (Sen technology, solvent: hexane / ethyl acetate The title compound (0.63 g, 2.1 mmol) of a yellow oily substance (yield 76%) was obtained from EtOAc EtOAc. 1H-NMR (500MHz, CD3C1) δ: 8.48 (2Η, d, J = 5 Hz), 7.77 (2H, d, J = 8 Hz), 7.19 (2H, d, J = 8 Hz), 7.08 ( 2H, d, J = 5 Hz), 3_98 (2H, s), 1.34 (12H, s). (2) {[(5-Hydroxy-6-methyl-2-{[4'-(pyridine-4) -ylmethyl)biphenyl-4-yl]methyl}pyrimidin-4-yl)carbonyl]amino}acetic acid imitation Example 6-1, replacing (4-chlorophenyl)boronic acid with [4-( Pyridin-4-ylmethyl)phenyl] The acid pinacol ester (0.63 g, 2.1 mmol) gave the title compound (0.16 g, <RTI ID=0.0></RTI> <RTIgt; DMSO-d6) 5 : 9.46 (1H, brs), 8.47 (2H, brs), 7.57 (2H, d, J = 7 Hz), 7.55 (2H, d, J = 7 Hz), 7.38 (2H, d, J = 8 Hz), 7.38 (2H, d, J = 8 Hz), 7.32 (2H, d, J = 8 Hz), 7.28 (2H, d, J = 4 Hz), 4.18 (2H, s), 4.00 (2H, d, J = 5 Hz), 3.99 (2H, s), 2.42 (3H, s). Example 47 {[(5-hydroxy-6-methyl-2-{[4'-(pyridine- 2-ylmethyl)biphenyl-4-yl]methyl}pyrimidin-4-yl)carbonyl]amino}acetic acid-172- 200948788

The title compound (0.090 g, 0.19 mmol), m. (yield 5.5%) MS m/z: 469 (M + H) + ; 1H-NMR (500MHz, DMSO-d6) δ: 9.43 (1H, brs), 8.48 (1H, brs), 7.71 (1H, t , J = 8 Hz), 7.54 (4H, d, J = 7 Hz), 7.38 (2H, d, J = 8 Hz), 7.34 (2H, d, J = 8 Hz), 7.31 (1H, d, J = 8 Hz), 7.21 (1H, t, J = 8 Hz), 4.17 (2H, s), 4.10 (2H, S), 3.98 (2H, d, J = 5 Hz), 2.42 (3H, s). Example 48 [({2-[4-(2-Tertiarypyrimidin-5-yl)benzyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

〇 (1) [4-(2-Tertiarypyrimidin-5-yl)phenyl]acetonitrile

Dissolve 5-bromo-2-tributylpyrimidine (1.9 g, 4.8 mmol) in Μ-dimethoxyethane (100 mL) and add [4-(4,4,5,5-tetramethyl) -1,3,2-dioxaborolan-2-yl)phenyl]acetonitrile (0.97 g, 4.0 mmol), [1,1,-bis(diphenylphosphino)ferrocene]palladium dichloride After methylene chloride complex (0.33 g, 0.40 mmol) and potassium phosphate hydrate (2.8 g, 12 mmol), the mixture was heated under reflux under nitrogen atmosphere - 173 - 200948788 1-5 hours. After cooling the reaction mixture to room temperature, hexane was added to filter the insoluble matter. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (yield solvent: hexane/ethyl acetate), and Rf 値=0.50 (hexane/ethyl acetate) The title compound (0.85 g, 3.3 mmol) was obtained as a yellow solid (yield: 85%). MS m/z : 252 (M + H)+ ;

lH-NMR (500MHz, CDC13) &lt;5: 8.91 (2H, s), 7.62 (2H, d, J = 7 Hz), 7.51 (1H, d, J = 7 Hz), 3.86 (2H, s), 1.49 (9H, s). (2) 2-[4-(2-Tertiarypyrimidin-5-yl)phenyl]ethyliminoamine acetate

This title compound (2.0 g, 6.0 mmol) (Quantity of yield). MS m/z : 269 (M + H)+ ;

(3) 5-(Benzyloxy)-2-[4-(2-tert-butylpyrimidin-5-yl)benzyl]-6-hydroxypyridin-4-carboxylic acid tert-butyl ester

Reference Example 1-(3), 2-[4-(2-T-butylpyrimidin-5-yl)phenyl]ethyliminoamine acetate (2.0 g, 6.0 mmol) 1.3 g, 2.5 mmol > yellow solid (yield 41%). 1H-NMR (500MHz, CDC13) &lt;5: 11.30 (1H, brs), 8.84 (1H, -174- 200948788 s), 7.52-7.43 (6H , m), 7.40-7.30 (3H, m), 5.25 (2H, s), 4.07 (2H, s), 1.46 (9H, s). (4) 5-(Benzyloxy)-2-[4- (2-tert-butylpyrimidin-5-yl)benzyl]-6-methylpyrimidine-4-carboxylic acid tert-butyl ester

Reference Example 2-(3), Reference Example 2-(4), 5-(Benzyloxy)-2-[4-(2-t-butylpyrimidin-5-yl)benzyl]-6- Hydroxypyrimidine-4-carboxylic acid tert-butyl ester (1.3 g, 2.5 mmol) gave the title compound (m. 1H-NMR (500MHz, CDC13) δ : 8.87 (1Η, s), 7.58-7.45 (4H, m), 7.44-7.33 (5H, m), 4.99 (2H, s), 4.31 (2H, s), 2.45 (3H, s), 1.46 (9H, s). (5) [({2-[4-(2-Tertiarypyrimidin-5-yl)benzyl]-5-hydroxy-6-methylpyrimidin-4-ylindolecarbonyl)amino]acetic acid imitation reference Example 2-(5), Example 44-(8), Example 1-(4), 5-(Benzyloxy)-2-[4-(2-tert-butylpyrimidin-5-yl) The title compound (0.52 g, 1.2 mmol MS m/z : 436 (M + H) + ; lH-NMR (500MHz, DMSO-d6) (5: 9.45 (1H, t, J = 5 Hz), 9.03 (2H, s), 7.69 (2H, d , J = 8 Hz), 7.46 (2H, d, J = 8 Hz), 7.43-7.34 (5H, m), 7.34-7.28 (2H, m), 4.21 (2H, s), 3.99 -175- 200948788 ( 2H,d,J = 5 Hz), 2.42 (3H, s), 1.38 (9H, s). Example 49 [({2-[4-(4-benzylpiperidin-1-yl)benzyl] -5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

(1) [4-(4-Benzylpiperidin-1-yl)phenyl]acetonitrile

Dissolve 4-benzylpiperidine (1.3 g, 7.2 mmol) in toluene (20 mL), add [4-(cyanomethyl)phenyl]boronic acid (1.1 g, 6.5 mmol), copper acetate (1) (0.24) g, 1.3 mmol), 2,6-dimethyl B ratio was steep (〇·77 g, 7.2 mmol), tetradecanoic acid (0.60 g, 2.6 mmol), and stirred at room temperature for 11.5 hours. After the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (lihhhhhhhhhhhhh The title compound (0.71 g, 2.4 mmol) was obtained as a white solid (yield: 38%). lH-NMR (500MHz, CDC13) 5 : 7.46-7.19 (5H, m), 7.16 (2H, d, J 2 8 Hz), 6.90 (2H, d, J = 8 Hz), 3.65 (2H, s), 2.65 (2H, t, J = 13 Hz), 2.58 (2H, d, J = 7 Hz), 1.75 (2H, d, J = 13 Hz), 1.70-1.60 (1H, m), 1.40 (2H, q , J = 13 Hz), 0.88 (2H, t, 7 Hz). (2) 2-[4-(4-Benzylpiperidin-1-yl)phenyl]ethyliminoamine acetate

NH AcOH -176- 200948788 </ RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 3.1 mmol) white solid (quantitative yield). MS m/z : 308 (M + H) + ;. (3) 5-(Benzyloxy)-2-[4-(4-benzylpiperidin-1-yl)benzyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester

Reference Example 1-(3), 2-[4-(4-Benzylpiperidin-1-yl)phenyl]ethyliminoamine acetate (1.2 g, 3.1 mmol) 0,20 g, 0.35 mmol) yellow solid (yield 11%). 1H-NMR (500MHz, CDC13) 5 : 7.44 (2H, d, J = 7 Hz), 7.38-7.15 (7H, m), 7.17 (2H, d, J = 7 Hz), 7.11 (2H, d, J = 8 Hz), 6.90 (2H, d, J = 7 Hz), 5.23 (2H, s), 3.94 (2H, s), 3.67 (2H, d, J =12 Hz), 2.69 (2H, t, J = 10 Hz), 2.60 (2H, d, J = 〇7 Hz), 1.75 (2H, d, J = 13 Hz), 1.70-1.60 (1H, m), 1.52 (9H, s), 1·40 ( 2H, q, J = 13 Hz). (4) [{5-(Benzyloxy)-2-[4-(4-benzylpiperidin-1-yl)benzyl]-6-methylpyrimidin-4-yl}carbonyl)amino] Ethyl acetate

Reference Example 2-(5), Reference Example 2-(3), Reference Example 2-(4), 5-(hydroxy)-2-[4-(4-benzylpiperidin-1-yl) Benzyl]-6-hydroxypyrimidine-4-carboxylic acid -177-200948788 Tributyl ester (0.20 g, 0.35 mmol). . 1H-NMR (500MHz, CDC13) δ 8.34 (1Η, t, J = 7 Hz), 7.93-7.86 ( 1 H, m), 7.70-7.62 (1H, m), 7.47 (2H, d, J = 7 Hz ), 7.46-7.20 (6H, m), 7.16 (2H, d, J = 7 Hz), 6.87 (2H, d, J = 7 Hz), 5.07 (2H, s)' 4.26 (2H, q, J = 8 Hz), 4.20 (d, J = 7 Hz), 4.14 (2H, s), 3.62 (2H, d, J = 12 Hz), 2.61 (2H, t,

J = 12 Hz), 2.57 (2H, d, J = 8 Hz), 2.43 (3H, s), 1.74 (2H, d, J = 12 Hz), 1.70- 1.60 (1H, m), 1.31 (3H, t, J = 8 Hz), 1.26 (2H, t, J = 7 Hz). (5) [({2-[4-(4-Benzylpiperidin-1-yl)benzyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid

Example 44-(8), Example 1-(4), using [{5-(benzyloxy)-2-[4-(4-benzylpiperidin-1-yl)benzyl]_6- Ethyl acetate (0.14 g, 0.24 mmol MS m/z : 475 (M + H) + ; lH-NMR (500MHz, DMSO-d6) (5: 12.86 (1H, brs), 11.91 (1H, s), 9.43 (1H, t, J = 5 Hz ), 7.31-7.25 (2H, m), 7.21-7.14 (3H, m), 7.12 (2H, d, J = 8 Hz), 6.82 (2H, d, J = 8 Hz), 4.01 (2H, s) , 4.00 (2H,d, J = 5 Hz), 3.59 (2H,d, J = 13 Hz), 2.40 (3H, s), 2.05- 1.95 (1 H, m), 1.68- 1.57 (4H, m) , 1.33-1.20 (4H, m). -178- 200948788 Example 50 [({5·Hydroxy-6-methyl-2-[4-(4-phenylpiperidin-1-yl)benzyl]pyrimidine -4-yl}carbonyl)amino]acetic acid

(l) [4-(4-Phenylpiperidin-1-yl)phenyl]acetonitrile

Example 49-(1), 4-benzylpiperidine was replaced with 4-phenylpiperidine (1.2 g, 7.2 mmol). %). lH-NMR (500MHz, CDC13) &lt;5: 7.46-7.19 (5H, m), 7.34 (2H, d, J = 8 Hz), 6.97 (2H, d, J = 8 Hz), 3.67 (2H, s ), 2.84 (2H, t, J = 13 Hz), 2.71-2.61 (1H, m), 2.35 (2H, d, J = 7 Hz), 1.89 (2H, d, J = 13 Hz), 1.40- 1.30 (2H, m), 0.88 (2H, t, 7 〇Hz) 〇(2)2-[4-(4-Phenylpiperidin-1-yl)phenyl]ethyliminoamine acetate

Reference Example 4-(4), 4-(4-Benzylpiperidin-1-yl)phenyl]acetonitrile was replaced by [[4-(4-phenylpiperidin-1-yl)phenyl] The title compound (0.82 g, 2.3 mmol. MS m/z : 294 (M + H)+. -179- 200948788 (3) 5-(Benzyloxy)-6-hydroxy-2-[4-(4-phenylpiperidin-1-yl)benzyl]pyrimidine-4-carboxylic acid tert-butyl ester

Reference Example 1-(3), 2-[4-(4-Phenylpiperidin-1-yl)phenyl]ethyliminoamine acetate (0.82 g, 2.3 mmol) g, 0.40 mmol) yellow oily material (yield 17%). MS m/z : 551 (M + H) + ; 1H-NMR (500MHz, CDC13) &lt;5: 7.44 (2H, d, J: 7 Hz), 7.38-7.15 (7H, m), 7.26-7.18 ( 1H, m), 7.17 (2H, d, J = 7

Hz), 6.95 (2H, d, J = 7 Hz), 5.24 (2H, s), 3.96 (2H, s), 3.82 (2H, d, J =12 Hz), 2.85 (2H, t, J = 10 Hz), 2.72-2.64 (1H, m), 1.75 (2H, d, J = 13 Hz), 1.53 (9H, s), 1.45 (2H, q, J = 13 Hz). (4) [{5-(Benzyloxy)-6-methyl-2-[4-(4-phenylpiperidin-1-yl)benzyl]pyrimidin-4-yl}carbonyl)amino]acetic acid Ethyl ester

Reference Example 2-(5), Reference Example 2-(3), Reference Example 2-(4), using 5·(benzyloxy)-2-[4-(4-phenylpiperidin-1-yl) The title compound (0.12 g, 0.21 mmol 1H-NMR (500MHz, CDC13) 5 : 8.36 (1H, t, J = 7 Hz), -180- 200948788 7.93-7.86 ( 1H, m), 7.70-7.62 (1 H, m), 7.48 (2H, d , J = 7 Hz), 7.46-7.20 (6H, m), 7.24 (2H, d, J = 7 Hz), 6.94 (2H, d, J = 7 Hz), 5.08 (2H, s), 4.21 (2H , q, J = 8 Hz), 4.20 (d, J = 7 Hz), 4.17 (2H, s), 3.78 (2H, d, J = 12 Hz), 2.79 (2H, t, J = 12 Hz), 2.68-2.54 ( 1H, m), 2.45 (3H, s), 2.00-1.91 (2H, m), 1.91 (2H, d, J = 12 Hz), 1.32 (3H, t, J = 8 Hz). (5) [({5-Hydroxy-6-methyl-2-[4-(4-phenylpiperidin-1-yl)benzyl]pyrimidin-4-yl}carbonyl)amino]acetic acid

Example 44-(8), Example (4), using [{5-(benzyloxy)-2-[4-(4-phenylpiperidin-bu)benzyl]-6- Ethylpyrimidin-4-yl}carbonyl)amino]acetate (0.12 g, 0.21 mmol) MS m/z : 461 (M + H) + ; lH-NMR (500MHz, DMSO-d6) 5 : 12.87 (1H, brs), 11.92 (1H, s), 9.45 (1H, t, J = 5 Hz) , 7.31-7.18 (5H, m), 7.16 (2H, d, J = 8 Hz), 6.90 (2H, d, J = 8 Hz), 4.04 (2H, s), 4.01 (2H, d, J = 5 Hz), 3.74 (2H, d, J = 13 Hz), 2.76-2.59 ( 1 H, m), 2.42 (3H, s), 1.89-1.81 (4H, m), 1.80- 1.69 (4H, m). Example 5 1 [({5-Hydroxy-6-methyl-2-[(trans-4-phenylcyclohexyl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid]

(1) (4-phenylcyclohexyl)acetonitrile -181- 200948788

Diethyl cyanomethylphosphonate (3.7 g, 22 mmol) was dissolved in tetrahydrofuran (50 mL), and a solution of lithium hexamethyldiazane in tetrahydrofuran (1 M, 23) was added at -78 ° C under nitrogen atmosphere. After mL, 23 mmol), stir at the same temperature for 1 hour. After adding a solution of 4-phenylcyclohexanone (3.0 g, 17 mmol) in tetrahydrofuran (10 mL), the mixture was stirred at room temperature for 30 minutes and stirred at 0 ° C for 2 hours. The reaction solution was poured into water, extracted with ethyl acetate, and the extract was washed with a saturated aqueous solution of sodium chloride. The solvent was evaporated under reduced pressure to give (4-phenylcyclohexylidene) acetonitrile. This was dissolved in ethyl acetate (1 〇〇 mL)' and 5% palladium on activated carbon (0.60 g) was added, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (Sentech Co., Ltd., elution solvent: hexane/ethyl acetate), and was subjected to Rf 値 = 0.65 (hexane/ethyl acetate = 5/1). The title compound (3.3 g, 17 mmol. MS m/z: 200 (M + H)+. (2) 2-(4-Phenylcyclohexyl)ethyliminoamine acetate

The title compound (4.5 g, 16 mmol) was obtained as a white solid (yield of yield) with 4-phenylcyclohexanone (3.2 g, 16 mmol). 1H-NMR (400MHz, DMSOd6) ό : 7.29 (2Η, t, J = 7 Hz), 7.27-7.17 (3H, m), 4.54 (1H, brs), 3.71 (2H, s), 2.60-2.45 (2H , m), 2.27 (1H, d, J = 8 Hz), 1.94 (2H, d, J = 12 Hz), 200948788 1.78-1.61 (4H, m), 1.51 (1H, q, J = 12 Hz), 1.31 (1H, q, J = 12 Hz), 1. 16 (1H, q, J = 12 Hz). (3) 5-(Benzyloxy)-6-hydroxy-2-[(4-phenylcyclohexyl)methyl]pyrimidine-4-carboxylic acid tert-butyl ester

Using the title compound (4.7 g, 9.9 mmol 62%). lH-NMR (400MHz, CDC13) 5 : 7.48 (2H, d, J = 8 Hz), 7.38- 7.32 (2H, m), 7.29-7.23 (4H, m), 7.18 (1H, d, J = 7 Hz ), 7.15 (1H, d, J = 7 Hz), 5.26 (2H, s), 2.83 (1H, d, J = 8 Hz), 2.64 (1H, d, J = 7 Hz), 2.61 (1H, m ), 2.43 (1H, m), 1.96- 1.65 (6H, m), 1.53 (9H, s), 1.48 (1H, m), 1.25 (1H, m). (4) 5-(Benzyloxy)-6-methyl-2.[(trans-4-phenylcyclohexyl)methyl]pyrimidine-4-carboxylic acid tert-butyl ester

Reference Example 2-(3), Reference Example 2-(4), 5-(Benzyloxy)-6-hydroxy-2-[(4-phenylcyclohexyl)methyl]pyrimidine-4-carboxylic acid The title compound (0.33 g, 0.70 mmol) m. lH-NMR (400MHz, CDC13) (5: 7.43-7.36 (4H, m), 7.30-7.26 -183- 200948788 (3H,m), 7.21 (2H, 4, J = 8 Hz), 7.17 (1H, t , J = 8 Hz), 5.01 (2H, s), 2.86 (2H, d, J = 7 Hz), 2.52-2.50 (1H, m), 2.46 (3H, s), 2.03- 1.98 (1H, m) , 1.90 (2H, d, J = 13 Hz), 1.83 (2H, d, J = 13 Hz), 1.59 (9H, s), 1.50 (2H, q, J = 13 Hz), 1.26 (2H, q, J = 12 Hz) (5) [(丨5-(Benzyloxy)-6-methyl-2-[(trans-4-phenylcyclohexyl)methyl]pyrimidin-4-yl}carbonyl)amine Ethyl acetate

Example 18-(4), using 3-(benzyloxy)-6-methyl-2-[(trans-4-phenylcyclohexyl)methyl]pyrimidine-4-carboxylic acid tert-butyl ester ( The title compound (0.20 g, 0.40 mmol. Thin layer chromatography Rf 値 = 0.44 (hexane / ethyl acetate = 2 / 1); lH-NMR (400 MHz, CDC13) 5 : 8.39 (1H, s), 7.49 (2H, d J = 8 Hz), 7.40 -7.33 (3H, m), 7.30 (2H, d, J = 8 Hz), 7.22-7.17 (3H, m), 5.12 (2H, s), 4.30-4.25 (4H, m), 2.86 (2H, d , J = 7 Hz), 2.50 (1H, m), 2.47 (3H, s), 2.05-1.97 (1H, m), 1.92 (2H, d, J = 13 Hz), 1.83 (2H, d, J = 13 Hz), 1.52 (2H, q, J = 13 Hz), 1.32 (3H, t, J = 7 Hz), 1.27 (2H, q, J 2 13 Hz). (6) [({5-Hydroxy-6-methyl-2-[(trans-4-phenylcyclohexyl)methyl]pyrimidin-4-yl}carbonyl)amino]ethyl acetate

-184- 200948788 Example 1-(3), using [({5-(benzyloxy)-6-methyl-2-[(trans-4-phenylcyclohexyl)pyrimidin-4-yl}carbonyl) Ethyl acetate ethyl ester (350 mg, 0.69 mmol). Thin layer chromatography Rf 値 = 0.13 (hexane/ethyl acetate = 2/1); 1H-NMR (400 MHz, CDC13) δ: 11.34 (1 Η, s), 8.49 (1H, t,

J 2 5 Hz), 7.30-7.26 (2H, m), 7.21 (2H,d, J = 7 Hz), 7.17 (1H, t, J = 7 Hz), 4.30 (2H, q, J = 7 Hz) , 4.22 (2H, d, J = 5 Hz), 2.79 (2H, d, J = 7 Hz), 2.54 (3H, s), 2.53-2.46 (1H, m), 1.98- 1.93 (1H, m), 1.91 (2H, d, J = 13 Hz), 1.83 (2H, d, J = 13 Hz), 1.50 (2H, q, J = 13 Hz), 1.33 (3H, t, J = 7 Hz), 1.25 ( 2H, q, J = 13 Hz). (7) [({5-Hydroxy-6-methyl-2-[(trans-4-phenylcyclohexyl)methyl]pyrimidin-4-yl}carbonyl)amino]acetic acid imitation Example 1-(4) ), using [({5-hydroxy-6-methyl-2-[(trans-4-phenylcyclohexyl)methyl]pyrimidin-4-yl}carbonyl)amino]acetate (280 mg, 0.69 The title compound (220 mg, 0.57 mmol. Mp 2 04 〇C ; MS m/z : 384 (M + H) + ; Calculated 値 analysis C21H25N304 : C, 65.7 8 ; H, 6.57; N, 10.96. Measured 値: C, 65.75 ; H, 6.51 ; 10.97 ; 1H-NMR (400MHz, CDC13)5 : 11.26 (1H, s), 8.50 (1H, t, J = 5 Hz), 7.29 (2H, d, J = 7 Hz), 7.21-7.16 (3H, m ), 4.31 -185- 200948788 (2H, d, J = 6 Hz), 2.80 (2H, d, J = 7 Hz), 2.55 (3H, s), 2.49 (1H, m), 1.97- 1.92 (1H, m), 1.91 (2H, d, J = 13 Hz), 1.83 (2H, d, J = 13 Hz), 1.49 (2H, q, J = 13 Hz), 1.24 (2H, q, J = 1 3 Hz) ). Example 52 {[(5-Hydroxy-2-{[trans-4-(4-hydroxyphenyl)cyclohexyl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid

(1) 5-(Benzyloxy)-6-hydroxy-2-{[4-(4-hydroxyphenyl)cyclohexyl]methyl}pyrimidine-4-carboxylic acid tert-butyl ester

Example 44-(1), Reference Example 4-(4), Reference Example 1-(3), 4-[4-(benzyloxy)phenyl]cyclohexanone (3.0 g, 11 mmol), The title compound (2.4 g, 4.8 mmol. MS m/z: 491 (M + H)'. (2) 2-{[4-(4-Ethyloxyphenyl)cyclohexyl]methyl}-5-(benzyloxy)-6-methylpyridin-4-carboxylic acid tert-butyl ester

Reference Example 2-(2) to Reference Example (4), 5-(benzyloxy)-6-hydroxy-2-{[4-(4-hydroxyphenyl)cyclohexyl]methyl}pyrimidine-4 - carboxylic acid tert-butyl ester (2.4 g, -186 - 200948788 4.8 mmol) afforded the title compound (2. MS m/z : 53 1 (M + H)+ ; <reverse: high polarity &gt; lH-NMR (500 MHz, CDC13) 5 : 7.43-6.97 (9H, m), 5.01 (2H, s), 2.85 (2H , d, J = 7 Hz), 2.62-2.45 ( 1H, m), 2.46 (3H, s), 2.28 (3H, s), 1.90-1.20 (9H, m), 1.59 (9H, s). : low polarity &gt; lH-NMR (500 MHz, CDC13) &lt;5: 7.43-6.97 (9H,

m), 5.00 (2H, s), 3.04 (2H, d, J = 8 Hz), 2.62-2.45 (1H, m), 2.45 (3H, s), 2.29 (3H, s), 1.90-1.20 (9H , m), 1.58 (9H, s). (3) {[(5-(Benzyloxy)-2-{[4-(4-hydroxyphenyl)cyclohexyl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid Ethyl ester

Reference Example 2-(5), using 2-{[4-(4-ethyloxyphenyl)cyclohexyl]methyl b-5(benzyloxy)-6-methylpyrimidine-4-carboxylic acid Tributyl ester (2.2 g, 4.2 mmol) gave the title compound (l. MS m/z : 5 18 (M + H) +. (4) {[(2-{[trans-4-(4-ethyloxyphenyl)cyclohexyl]methyl}-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid Ethyl ester

{[(5-Benzyloxy-2-{[4-(4-hydroxyphenyl)cyclohexyl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}ethyl acetate (0.23 g, 0.44 mmol) was dissolved in ethyl 187-200948788 ethyl acetate (10 mL), 5% palladium-activated carbon (0.020 g), and stirred under a hydrogen atmosphere at room temperature for 0.5 hour. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. The obtained white solid was dissolved in dichloromethane (10 mL). EtOAc (EtOAc,EtOAc. After adding hydrochloric acid (1 Torr, 10 mL) to the reaction mixture, organics were evaporated. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ssssssssssssssssssssssssssssssssssssssss 2/1) Concentration under reduced pressure to obtain a mixture of diastereomers {[(2_{[4-(4-ethyloxyphenyl)cyclohexyl]methyl b 5 hydroxy-6-methyl Pyrimidin-4-yl)carbonyl]amino} Ethyl acetate (0.17 g, 0.36 mmol) as a white solid (yield: 82%). This was refined by sand column chromatography (GL Science, Inertsil ODS-3, elution solvent · acetonitrile / 0.1% aqueous ammonium acetate = 70/30), and concentrated under reduced pressure corresponding to the highly polar compound. The title compound was obtained as a white solid (yield: 58%).

lH-NMR (500MHz, CDC13) 5 : 11.33 (1H, s), 8.51 (1H, t, J = 5 Hz), 7.19 (2H, d, J = 8 Hz), 6.98 (2H, d, J = 8 Hz), 4.28 (2H, q, J = 7 Hz), 4.22 (2H, d, J = 5 Hz), 2.78 (2H, d, J = 7 Hz), 2.54 (3H, s), 2.51-2.45 ( 1H, m), 2.28 (3H, s), 1.95-1.20 (9H, m), 1.33 (3H, t, J = 7 Hz). (5) {[(5-Hydroxy-2-{[trans-4-(4-hydroxyphenyl)cyclohexyl]methyl) 6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid imitation example 1-(4)' with {[(2-{[trans-4-(4-ethyloxyphenyl)cyclohexyl]) 188- 200948788 methyl}-5-hydroxy-6-methylpyrimidine-4- Ethyl acetate (amino) ethyl acetate (0.10 g, 0.21 mmol, EtOAc) MS m/z: 400 (M + H) + ; lH-NMR (500MHz, DMSO-d6) (5: 11.90 (1H, s), 9.36 (1H, t, J = 6 Hz), 9.08 (1H, s ), 6.99 (2H, d, J = 8 Hz), 6.64 (2H, d, J = 8 Hz), 3.99 (2H, d, J = 6 Hz), 2.72 (2H, d, J = 7 Hz), 2.43 (3H, s), 2.37-2.33 (1H, m), 2.00-1.11 (9H, m).

Example 53 {[(2-{[Ret-4-(4'-fluorobiphenyl-4-yl)cyclohexyl]methyl) 5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino }Acetate

(1) ({[5-(Benzyloxy)-6-methyl]2-{[trans-4-(4-{[(trifluoromethyl)sulfonyl)oxy}phenyl)cyclohexyl Methyl}pyrimidin-4-yl]carbonyl oxime) ethyl acetate

Referring to Example 2-(3), {[(5-benzyloxy-2-{[4-(4-hydroxyphenyl)cyclohexyl]methyl) 6-methyl was obtained using Example 52-(3). Ethylpyrimidin-4-yl)carbonyl]amino}acetate (0.50 g, 1.0 mmol) 1H-NMR (500MHz, CDC13) δ : 8.36 (1Η, brs), 7.48 (2H, d, J = 7 Hz), 7.39-7.34 (3H, m), 7.26 (2H, d, J = 7 Hz), 7.18 -189- 200948788 (2H, d, J = 7 Hz), 5.12 (2H, s), 4.28 (2H, q, J = 7 Hz), 4.24 (2H, d, J = 5 Hz), 2.85 (2H , d, J = 7 Hz), 2.57-2.50 (1H, m), 2.46 (3H, S), 2.04-1.96 (1H, m), 1.90 (2H, d, J = 12 Hz), 1.84 (2H, d, J = 12 Hz), 1.51-1.43 (2H, m), 1.32 (3H, t, J = 7 Hz), 1.32-1.24 (2H, m) » (2){[(2-{[反· 4-(4'-fluorobiphenyl-4-yl)cyclohexyl]methyl}-5.hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid imitation Example 6-(1), Example 1-(3), Example 1-(4), using ({[5-(benzyloxy)-6-methyl-2-{[trans-4-(4-{[(trifluoromethyl)) Ethylsulfonyl]oxy)phenyl)cyclohexyl]methyl}pyrimidin-4-yl]carbonyl}amino)acetate (〇.17 g, 0.26 mmol) and 4-fluorophenylboronic acid (0.073) g, 0, 52 mmol) gave the title compound (0.060 g, 0.13 MS m/z: 478 (M + H) + ; 1H-NMR (500MHz, DMSO-d6) &lt;5: 11.91 (1H, brs), 9.37 (1H, s), 7.66 (2H, d, J = 9 Hz), 7.54 (2H, d, J = 8 Hz), 7.30 (2H, d, J = 8 Hz), 7.26 (2H, t, J = 9 Hz), 4.00 (2H, d, J = 6 Hz) , 2.76 (2H, d, J = 7 Hz), 2.57-2.47 (1H, m), 2.44 (3H, s), 2.03- 1.94 (1H, m), 1.82 (2H, d, J = 12 Hz), 1.76 (2H, d, J = 12 Hz), 1.48 (2H, dt, J = 12 Hz, 12 Hz), 1.26-1.16 (2H, m) Example 54 {[(5-hydroxy-2-{[反-4-(2'-hydroxybiphenyl-4-yl)cyclohexyl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid-190- 200948788

Example 53-(2), obtained using Example 53-(1) (([5-(benzyloxy)-6-methyl-2-{[trans-4·(4-{[(trifluoro)) Methyl)sulfonyl]oxy}phenyl)cyclohexyl]methyl}pyrimidin-4-yl]carbonyl}amino)acetate (0.17 g, 0.26 mmol) and [2-(benzyloxy)benzene The title compound (0.011 g, 0.023 mmol) was obtained as a white solid (yield: 8.9%). Λ MS m/z: 476 (M + H) + ; Ο 1H-NMR (500 MHz , DMSO-d6) &lt;5 : 9.44 (1H, s), 9.37 (1H, brs), 7.43 (2H,d,J = 8 Hz), 7.23 (2H, d, J = 8 Hz), 7.20 (1H , d, J = 7 Hz), 7.12 (1H, t, J = 7 Hz), 6.92 (1H, d, J = 7 Hz), 6.84 (1H, t, J = 7 Hz), 3.99 (2H, d , J = 5 Hz), 3.68 (1H, brs), 2.76 (2H, d, J = 7 Hz), 2.44 (3H, s), 2.03-1.95 (1H, m), 1.82 (2H, d, J = 12 Hz), 1.76 (2H, d, J = 12 Hz), 1.53-1.41 (2H, m), 1.25-1.16 (2H, m). Example 5 5 U(2-{[reverse-4-( 4-benzylindole phenyl)cyclohexyl]methyl b 5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid

(1) 5-(Benzyloxy)-6-methyl-2-{[trans-4-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)cyclohexyl]methyl }pyrimidine-4-carboxylic acid tert-butyl ester-191- 200948788

Imitative Example 1-(4), Reference Example 2-(3), 2-{[4-(4-Ethyloxyphenyl)cyclohexyl]methyl b-(5) obtained by Reference Example 2-(4) Benzyloxy)-6-methylpyrimidine-dicarboxylic acid tert-butyl ester (1 - EtOAc, EtOAc, EtOAc) 1H-NMR (500MHz, CDC13) &lt;5: 7.42-7.36 (5H, m), 7.34 (2H, d, J = 8 Hz), 7.20 (2H, d, J = 8 Hz), 5.00 (2H, s ), 3.04 (2H, d, J = 8 Hz), 2.67-2.61 (1H, m), 2.51-2.45 (1H, m), 2.45 (3H, s), 1.87- 1.78 (2H, m), 1.72- 1.62 (6H, m), 1.58 (9H, s). (2) 2-{[trans-4-(4-benzylphenyl)cyclohexyl]methyl}-5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid tert-butyl ester

5-(Benzyloxy)-6-methyl-2-{[trans-4-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)cyclohexyl]methyl}pyrimidine 4-carboxylic acid tert-butyl ester (0.50 g, 0.81 mmol) was dissolved in methoxybenzene (20 mL), and then, under nitrogen atmosphere, potassium iodide (0.44 g, 2.4 mmol), potassium carbonate (0.37 g, 2.4 mmol) After phenylboronic acid (0.13 g, 0.97 mmol) and [1,1,-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.072 g, 0.081 mmol), The mixture was heated and stirred at 80 ° C for 5 hours under a carbon monoxide atmosphere. After the reaction solution was cooled to room temperature, the insoluble matter was filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (Sen Technology-192-200948788, solvent: hexane/ethyl acetate), and Rf 値 = 0.50 with thin layer chromatography (hexane/ethyl acetate = 2/1) The title compound (0.22 g, 0.38 mmol)yield (yield: 47%). 1H-NMR (500MHz, CDC13) δ 7.79 (2Η, d, J = 7 Hz), 7.75 (2H, d, J = 7 Hz), 7.59-7.34 (8H, m), 7.31 (2H, d, J = 7 Hz), 5.01 (2H, s), 2.88 (2H, d, J = 7 Hz), 2.64-2.57 (1H, m), 2.47 (3H, s), 2.08- 1.98 (1H, m), 1.92 ( 2H, d, J = 12 Hz), 〇 1.86 (2H, d, J = 12 Hz), 1.59 (9H, s), 1.57-1.49 (2H, m), 1'30-1_22 (2H, m). (3) {[(2-{[trans-4-(4-benzylphenyl)cyclohexyl]methyl}-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid imitation Reference Example 2-(5), Example 44-(8), Example 1-(4), using 2-{[trans-4-(4-indolylphenyl)cyclohexyl]methyl}-5- (Alkoxy)-6-methyloxime- 4 - carboxylic acid tert-butyl ester (0.22 g, 0.38 mmol) mp. ). MS m/z: 488 (M + H) + ; 1H-NMR (500MHz, DMSO-d6) δ: 11.91 (1H, brs), 9.37 (1H, t, J = 5 Hz), 7.72 (2H, d, J = 8 Hz), 7.68-7.65 (1 H, m),

7.66 (2H, d, J = 8 Hz), 7.55 (2H, t, J = 8 Hz), 7.42 (2H, d, J = 8 Hz), 4.00 (2H, d, J = 5 Hz), 2.76 ( 2H, d, J = 7 Hz), 2.61 (1H, t, J = 12 Hz), 2.44 (3H, s), 2.04-1.95 (1H, m), 1.83 (2H, d, J = 12 Hz), 1.76 (2H, d, J = 12 Hz), 1.57- 1.45 (2H, -193- 200948788 m), 1.27-1.15 (2H, m). Example 56 {[(5-Hydroxy-6-methyl-2-{[trans-4-(4-pyridin-2-phenyl)cyclohexyl]methyl}pyrimidin-4-yl)carbonyl]amino} Acetic acid

(1) 5-(Benzyloxy)-6-methyl-2-{[trans-4-(4-pyridin-2-phenyl)cyclohexyl]methyl}pyrimidine-4-carboxylic acid tert-butyl ester

The 5-(benzyloxy)·6-methyl-2-{[trans-4-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl group obtained in Example 55-(1) Cyclohexyl]methyl}pyrimidine-4-carboxylic acid tert-butyl ester (0.26 g, 0.42 mmol) was dissolved in tetrahydrofuran (20 mL). EtOAc (triphenylphosphine) palladium (0.048 g) , 0.042 mmol) and a solution of 2-pyridylzinc bromide in tetrahydrofuran (0.50 M, 1.0 mL, 0.50 mmol). After a solution of hydrazine (triphenylphosphine) palladium (0.030 g, 0.026 mmol) and 2-pyridylzinc bromide in tetrahydrofuran (0.50 Μ, 1.0 mL, 0.50 mmol) was added, and the mixture was stirred for further 6 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (sssssssssssssssssssss The title compound (0.11 g, 0.20 mmol)yield (yield: 48%). 1H-NMR (500MHz, CDC13) δ : 8.67 (1Η, brs), 7.92 (2H, -194- 200948788 d, J = 7 Hz), 7.75 -7.69 (2H, m), 7.45-7.17 (8H, m) , 5.01 (2H, s), 2.88 (2H, d, J = 7 Hz), 2.60-2.51 (1H, m), 2.46 (3H, s), 2.08- 1.98 ( 1H, m), 1.92 (2H, d , J = 12 Hz), 1.84 (2H, d, J = 12 Hz), 1.59 (9H, s), 1.57- 1.49 (2H, m), 1.30- 1.23 (2H, m). (2) {[(5-Hydroxy-6-methyl-2-{[trans-4-(4-pyridin-2-phenyl)cyclohexyl]methyl}pyrimidin-4-yl)carbonyl]amino} Acetic acid

Reference Example 2-(5), Example 1-(3), Example 1-(4), 5-(benzyloxy)-6-methyl-2-{[trans-4-(4-) The title compound (0.067 g, 0.15 mmol MS m/z : 461 (M + H) + ; 1H-NMR (500MHz, DMSO-d6) δ: 9.37 (1H, brs), 8.63

(1H, brs), 7.98 (2H, d, J = 8 Hz), 7.91 (1H, d, J = 7 Hz), 7.85 (1H, t, J = 7 Hz), 7.34 (2H, d, J = 8 Hz), 7.31 (1H, d, J =7 Hz), 4.00 (2H, d, J = 5 Hz), 2.76 (2H, d, J = 7 Hz), 2.48-2.46 (1H, m), 2.44 (3H, s), 2.05 - 1.95 (1 H, m), 1.83 (2H, d, J = 13 Hz), 1.76 (2H, d, J = 13 Hz), 1.55 - 1.44 (2H, m), 1.27 -1.16 (2H, m). Example 57 {[(5-Hydroxy-6-methyl-2-{[trans-4-(4-pyridin-3-phenyl)cyclohexyl]methyl}pyrimidin-4-yl)carbonyl]aminopurine Acetic acid-195- 200948788

Example 56-(1), Example 44-(8), Example 1-(4), 5-(Benzyloxy)-6-methyl-2-{, obtained from Example 55-(1) [Reverse 4-(4-{[(trifluoromethyl))sulfonyl]oxy}phenyl)cyclohexyl]methyl}pyrimidine-4-carboxylic acid tert-butyl ester (0.20 g, 0.32 mmol) (3-La-Phenylphenyl)boronic acid (0.12 g, 1.0 mmol). MS m/z : 46 1 (M + H) + ; 1H-NMR (500MHz, DMSO-d6) &lt;5: 11.90 (1H, brs), 9.38 (1H, t, J = 6 Hz), 8.86 (1H , s), 8.54 (1H, d, J = 4 Hz), 8.04 (1H, d, J = 8 Hz), 7.62 (2H, d, J = 8 Hz), 7.46 (1H, dd, J = 8 Hz) , 4 Hz), 7.36 (2H, d, J = 8 Hz), 4.01 (2H, d, J = 5 Hz), 2.76 (2H, d, J = 7 Hz), 2.58-2.50 (1H, m), 2.44 (3H, s), 2.04- 1.94 (1H, m), 1.82 (2H, d, J = 13 Hz), 1.76 (2H, d, J = 13 Hz), 1.54- 1.43 (2H, m), 1.25 -1.16 (2H, m). Example 58 [({5-Hydroxy-6-methyl-2-[(trans-4-{4-[methyl(phenyl)amino]phenyl}cyclohexyl)methyl]pyrimidin-4-yl }carbonyl)amino]acetic acid

(1) 5-(Benzyloxy)-6-methyl-2-[(trans-4-{4-[methyl(phenyl)amino]phenyl}cyclohexyl)methyl]pyrimidine-4- Tert-butyl carboxylate•196- 200948788

5-(Benzyloxy)_6-methyl-2_{[trans-4-(4_{[(trifluoromethyl)sulfonyl)oxy}phenyl)cyclohexyl]-A obtained from Example 55-(1) Base}pyrimidine-4_carboxylic acid tert-butyl vinegar (0.30 g, 0.48 mmol), N-methylaniline (0.077 g, 0.73 mmol), sodium butoxide (ο′% g, U mmol), 2- Dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (S-PHOSK0.092 g, 0.19 mmol) 0 and ginseng (dibenzylideneacetone) dipalladium (0.088 g , 0.10 mmol) was suspended in toluene (12 mL), and stirred under nitrogen for 8 hr. After the reaction solution was cooled to room temperature, it was filtered through celite. After the filtrate was concentrated under reduced pressure, the residue obtained was purified by silica gel column chromatography (Sen technology, solvent: hexane/ethyl acetate), and Rf 値 = 0, 80 (hexane/acetic acid B) The title compound (0.080 g, 0.14 mm ο 1) pale yellow solid (yield 29%). MS m/z : 578 (M + H) + ;. Ο (2) [({5-Hydroxy-6-methyl-2-[(trans-4-{4-[methyl(phenyl)amino]phenyl}cyclohexyl)methyl]pyrimidine-4- Reference Example 2-(5), Example 1-(3), Example 1-(4), 5-(Benzyloxy)-6-methyl-2-[ (Reverse-4-{4-[methyl(phenyl)amino]phenyl}cyclohexyl)methyl]pyrimidine-4-carboxylic acid tert-butyl ester (0.080 g, 0.14 mmol) g, 0.041 mmol) yellow solid (yield 29%). MS m/z: 489 (M + H).; 1H-NMR (500MHz, DMSO-d6) &lt;5: 9.20 (1H, brs), 7.21 -197 - 200948788 (2H, t, J = 8 Hz), 7.15 (2H, d, J = 8 Hz), 6.96 (2H, d, J = 8 Hz), 6.89 (2H, d, J = 8 Hz), 6.84 (1H, t, J = 8 Hz), 3.83 ( 2H, brs), 3.21 (3H, s), 2.73 (2H, d, J = 7 Hz), 2.47-2.38 (1H, m), 2.43 (3H, s), 1.98- 1.89 (1 H, m), 1.78 (2H,d,J = 12 Hz), 1.73 (2H, d, J = 12 Hz), 1.50- 1.36 (2H, m), 1.23-1.13 (2H, m). Example 59 {[(5-Hydroxy-2-{[4-hydroxy-4-(4-phenoxyphenyl)cyclohexyl]methyl}-6-methylpyrimidin-4-yl)carbonyl]aminopurine Acetic acid

(1) 5-(Benzyloxy)-2-(1,4-dihydrospiro[4,5]decane-8-ylmethyl)-6-methylpyridin-4-carboxylic acid tert-butyl ester

Reference Example 4-(4), Reference Example 1-(3), using 1,4-dihydrospiro[4,5]decane-8-ylacetonitrile (8.6 g, 48 mmol) to give 5-(benzyl) Oxy)-2-(1,4-dioxaspiro[4,5]decane-8-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (14 g, 30 mmol) yellow Solid (yield 63%). Reference Example 2-(3), Reference Example 2-(4), 5-(Benzyloxy)-2-(1,4-dioxaspiro[4,5]decane-8-ylmethyl) 3-Hydroxypyrimidine-4-carboxylic acid tert-butyl ester (12 g, 25 mmol). -198- 200948788

lH-NMR (500MHz, CDC13) 5 : 7.45-7.32 (5H, m), 5.〇〇(2H s), 3.94(4H,s), 2.84(2H,d,J = 7Hz), 2.44(3H, s) '2〇2- 1.96 (1H, m), 1.79- 1.66 (4H, m), 1.60-1.51 (2H, m), ! 58 (9H, s), 1.46-1.36 (2H, m). (2) 5-(Benzyloxy)-6-methyl-2-[(4-oxycyclohexyl)methyl]pyrimust_4_residual acid tert-butyl ester

3-(Benzyloxy)-2-(1,4-dihydrospiro[4.5]decane-8-ylmethyl)-6-methylpyrimidine-4-carboxylic acid tert-butyl ester (13 g, 29 mmol), p-toluenesulfonic acid monohydrate (0.55 g, 2.9 mmol) and water (20 mL) were dissolved in acetone (400 mL) and stirred for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (yield solvent: hexane/ethyl acetate), and Rf 値=0.50 (hexane/ethyl acetate = The title compound (11 g, 28 mmol) white solid (yield: 96%). lH-NMR (500MHz, CDC13) 5 : 7.43-7.34 (5H, m), 5.01 (2H, s), 2.94 (2H, d, J = 7 Hz), 2.46 (3H, s), 2.44-2.32 (4H , m), 2.08-2.00 (1H, m), 1.61-1.52 (4H, m), 1.59 (9H, s). (3) 5-(Benzyloxy)-2-{[4-hydroxy-4-(4-phenoxyphenyl)cyclohexyl]methyl}-6-methylpyrimidine-4-carboxylic acid tert-butyl ester

-199- 200948788 Dissolve 3-(benzyloxy)-6-methyl-2.[(4-oxocyclohexyl)methyl]pyrimidine-4-carboxylic acid tert-butyl ester (1.0 g, 2.4 mmol) After a solution of 4-phenoxyphenylmagnesium bromide in tetrahydrofuran (0.50 M, 7.3 mL, 3.7 mmol) was added to THF (1 mL), and the mixture was stirred at room temperature for 2 hours. After adding a solution of 4-phenoxyphenylmagnesium bromide in tetrahydrofuran (0.50 M, 3.0 mL, 1.5 mmol) at -78 ° C, the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the mixture and the mixture was evaporated. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (yield, solvent solvent: hexane/ethyl acetate), and &lt;&gt; The title compound (1.2 g, 2.1 mmol) was obtained as a white solid (yield: 86%). MS m/z : 581 (M + H)+. (4) {[(5-Hydroxy-2-{[4-hydroxy-4-(4-phenoxyphenyl)cyclohexyl]methyl b 6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid Ethyl ester

仿 Reference Example 2-(5), Example 1-(3), 5-(Benzyloxy)-2-{[4-hydroxy-4-(4-phenoxyphenyl)cyclohexyl]methyl 6-Methylpyrimidine-4-carboxylic acid tert-butyl ester (1.2 g, 2.1 mmol) gave the title compound (0.60 g, 1.1 1H-NMR (500MHz, CDC13) &lt;5 : 1 1.34 (1H, s), 7 52 and 7 · 45 (for 2H, each t, J = 8 Ηζ), 7·37-7·31 (2H, m ), 7.13-6.96 (5H, m), 4.28 and 4.27 (for 2H, each q, J = 7 Hz), 4.22 and 4.20 (for 2H, each d, J = 6 Hz), 2.84 and 2.80 (for 2H, Each d, J = 7 Hz), -200- 200948788 2.54 and 2.52 (3 Η, each s), 2.36-2.32 and 2.25-2.16 (2 Η, each m), 2.04-1.57 (7H, m), 1.33 and 1.32 (count 3H, each t, J = 7 Hz). (5) {[(5-Hydroxy-2-U4-hydroxy-4-(4-phenoxyphenyl)cyclohexyl]methyl b 6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid hydrazine

Example 1-(4), using {[(5-hydroxy-2-{[4·hydroxy-4-(4-phenoxyphenyl)cyclohexyl]methyl b 6-methylpyrimidin-4-yl) Ethyl carbonyl]aminoacetate (0.040 g, 0.077 mmol). MS m/z: 492 (M + H) + ; 1H-NMR (500MHz, DMSO-d6) δ: 12.87 (1H, brs), 11.89 (1H, brs), 9.37 (1H, brs), 7.52, 7.48 ( 2H, d, J = 8 Hz), 7.41-7.36 (2H, m), 7.16-6.91 (5H, m), 4.76, 4.69 (1H, s), 4.01-3.98 (2H, brs) , 2.82-2.74 (calculated 2H, m), 2.44, 2.42 (count 3H, s), 2.27-1.13 (calculated 9H, m). Example 60 {[(5-Hydroxy-6-methyl-2-{[4-(4-phenoxyphenyl)cyclohex-3-en-1-yl]methyl}pyrimidin-4-yl)carbonyl) Amino}acetic acid

YH (1){[(5-Hydroxy-6-methyl-2-{[4-(4-phenoxyphenyl)cyclohex-3-en-1-yl]methyl}pyrimidin-4-yl) Carbonyl]amino}ethyl acetate-201 - 200948788

{[(5-Hydroxy-2-{[4-hydroxy-4-(4-phenoxyphenyl)cyclohexyl]methyl}-6-methylpyrimidin-4-yl) obtained in Example 59-(4) Ethyl carbonyl]amino}ethyl acetate (0.10 g, 0.19 mmol) was dissolved in benzene (5 mL), and 1,1,1-triethyl-3-(methoxycarbonyl)di K thiohexyl-1. The gun 2,2-dioxide (Burges Reagent) (0.10 g, 0.43 mmol) was stirred at 75 ° C for 5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Sen Technology Co., Ltd., elution solvent: hexane/ethyl acetate), and Rf 値 = 0.60 (hexane/ethyl acetate = 3/1) corresponding to thin layer chromatography. The title compound (0.065 g, 0.13 mmol. 1H-NMR (500MHz, CDC13) (5: 11.35 (1H, s), 8.51 (1H, brs), 7.35 (2H, d, J = 8 Hz), 7.32 (2H, t, J = 8 Hz), 7.08 OH, t, J = 8 Hz), 7.00 (2H, d, J = 8 Hz), 6.95 (2H, d, J = 8 Hz), 6.04 (1H, s), 4.28 (2H, q, J = 7 Hz), 4.22 (2H, d, J = 5 Hz), 2.87 (2H, brs), 2.54 (3H, s), 2.51-2.39 (2H, m), 2.32-2·22 (2H, m), 2.04 - 1.92 (2H, m), 1.55 - 1.48 ( 1H, m), 1.32 (3H, t, J = 7 Hz). [(5-Hydroxy-6-methyl-2-{[4-(4-phenoxyphenyl)cyclohex-3-en-1-yl]methyl}pyrimidin-4-yl)carbonyl]amino} Example 1-(4) of acetic acid, using {[(5-hydroxy-6-methyl-2-{[4-(4-phenoxyphenyl)cyclohex-3-en-1-yl]methyl Ethyl pyrimidine-4-yl)carbonyl]amino}acetate (0-025 g, 0.050 mmol) MS m/z: 474 (M + H) + ; 1H-NMR (500MHz, DMSO-d6) δ: 9.14 (1H, brs), 7.42 (2H, d, J = 8 Hz), 7.38 (2H, t, J = 8 Hz), 7.13 (1H, t, J = 8 Hz), 7.00 (2H, d, J = 8 Hz), 6.94 (2H, d, J = 8 Hz), 6.08 (1H, brs), 3.75 (2H, brs), 2.81 (2H, brs), 2.47-2.34 (2H, m), 2.42 (3H, s), 2.27-2.16 (2H, m), 1.99- 1.83 (2H, m), 1.46-1.38 (1H, m).

Example 6 1 {[(5-Hydroxy-6-methyl-2-{[4-(4-phenoxyphenyl)cyclohexyl]methyl}pyrimidin-4-yl)carbonyl]amino}acetic acid imitation Examples 1-(3), 1-(4), using {[(5-hydroxy-6-methyl-2-{[4-(4-phenoxyphenyl)cyclohexane) obtained in Example 60-(1) Ethyl acetate (0.034 g, 0.068 mmol) EtOAc (m. %). MS m/z : 476 (M + H) + ; 1H-NMR (500MHz, DMSO-d6) δ 11.90 (1H, brs), 9.37 (1 Η, brs), 7.39-6.90 (9 Η, m), 4.00 (2 Η, t, J = 5 Hz), 2.94, 2.74 (2H, d, J = 7 Hz), 2.62-2.39 (1H, m), 2.44, 2.43 (3H, s), 2.02- 1.14 (count 7H, m). Example 62 {[(2-{[4-(2-Tertiarypyrimidin-5-yl)cyclohex-3-en-1-yl]methyl b 5-hydroxy-203 - 200948788 base-6- Methylpyrimidin-4-yl)carbonyl]aminopurinic acid ΓΤ^νΊΠΓ°Η ν^οη δ

Dissolve 5-bromo-2-tributylpyrimidine (0.17 g, 0.78 mmol) in tetrahydrofuran (15 mL), and add a solution of n-butyllithium in hexane at -78 ° C (2.64 M, 0.28) After mL, 0.73 mmol), the mixture was stirred at the same temperature for 30 minutes to prepare a solution of 2-tert-butylpyrimidine bromide in tetrahydrofuran. With this, the 5-butyl benzyl 5-(benzyloxy)-6-methyl-2-[(4-oxocyclohexyl)methyl]pyrimidine-4-carboxylate obtained in Example 59-(2) (0.20) g, 0.49 mmol), imitation Example 59-(3), Example 60-(1), Reference Example 2-(5), Example 1-(3), Example 1-(4) (0.0080 g, 0.018 mmol) white solid (yield: 3.7%). MS m/z : 440 (M + H) + ; 1H-NMR (500MHz, DMSO-d6) &lt;5: 9.38 (1H, brs), 8.78 (2H, s), 6.28 (1H, s), 3.98 ( 2H, d, J = 6 Hz), 3.49-3.26 (2H, m), 2.83 (2H, brs), 2.44 (3H, s), 2.33-2.17 (2H, m), 2.01- Q 1.71 (2H, m ), 1.49-1.38 (1H, m), 1, 34 (9H, s). Example 63 {[(2-{[Ret-4-(4-fluorophenoxy)cyclohexyl]methyl}-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid ( 1) ({ [5-(Benzyloxy)-2-(1,4-dioxaspiro[4,5]decane-8-ylmethyl)-6-methylpyrimidin-4-yl]carbonyl} Amino) Ethyl Acetate-204- 200948788 cr^X\ri Imitation Reference Example 4-(4), Reference Example 1-(3), using 1,4-disulfonium [4,5]nonane-8 Acetonitrile (8.6 g, 48 mmol) gave 5-(hydroxy)-2-(1,4-di-spiro[4,5]nonane-8-ylmethyl)-6-hydroxypyrimidine-4 -carboxylic acid ethyl (14 g, 30 mmol) yellow solid (yield: 63%).

Reference Example 2-(3) to Reference Example 2-(5), using 5-(benzyloxy)-2-(1,4-dioxaspiro[4,5]decane-8-ylmethyl) Ethyl-6-hydroxypyrimidine-4-carboxylate (12 g, 25 mmol). lH-NMR (500MHz, CDC13) 5 : 8.36 (1H, t, J = 5 Hz), 7.50-

7.45 (2H, m), 7.40-7.32 (3H, m), 5.11 (2H, s), 4.27 (2H, q, J

=8 Hz), 4.23 (2H, d, J = 5 Hz), 3.94 (4H, s), 2.84 (2H, d, J =7 Hz), 2.45 (3H, s), 2.02-1.96 (1H, m ), 1.79-1.72 (2H, m),

1.72- 1.65 (2H, m), 1.60-1.51 (2H, m), 1.46-1.36 (2H, m), 1.32 (3H, t, J = 8 Hz). (2) [({5-(Benzyloxy)-6-methyl-2-[(4-oxycyclohexyl)methyl]pyrimidin-4-yl}carbonyl)amino]acetate

Example 59-(2), using ({[5-(benzyloxy)-2-(1,4-dioxaspiro[4,5]decane-8-ylmethyl)-6-methyl Ethylpyrimidin-4-yl]carbonyl}amino)acetate (7.1 g, 15 mmol) lH-NMR (500MHz, CDC13) 5 : 8.34 (1H, t, J = 5 Hz), 7.52- 7.45 (2H, m), 7.43-7.32 (3H, m), 5.12 (2H, s), 4.27 (2H , q, J =8 Hz), 4.24 (2H, d, J = 5 Hz), 2.93 (2H, d, J = 8 Hz), 2.47 (3H, s), 2,47-2.33 (4H, m) , 2.08-1.99 (1H, m), 1.64-1.51 (4H, m), 1.32 (3H, t, J = 8 Hz). (3) [(5 5-(Benzyloxy)-2-[(trans-4-hydroxycyclohexyl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]ethyl acetate

[({5-(Benzyloxy)-6-methyl-2-[(4-oxycyclohexyl)methyl]pyrimidin-4-yl}carbonyl)amino]acetate (0.88 g, 2.0 Methyl acetate was dissolved in tetrahydrofuran (10 mL), and a solution of tris(t-butyl)borohydride in tetrahydrofuran (1.0 M, 2.0 mL, 2.0 mmol) was then evaporated. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The obtained residue was purified by silica gel column chromatography (Sentech Co., Ltd., solvent: hexane/ethyl acetate), and concentrated under reduced pressure of 〇 and Rf 値 = 0.40 (ethyl acetate) of thin layer chromatography. The title compound (0.18 g, 0.40 mmol. lH-NMR (5〇〇MHz, CDC13) 5 : 8.39 (1H, t, J = 6 Hz), 7.52- 7.46 (2H, m), 7.42-7.32 (3H, m), 5.11 (2H, s), 4.27 (2H, q, J =7 Hz), 4.24 (2H, d, J = 6 Hz), 4.03-3.96 (1H, m), 2.86 (2H, d, J = 7 Hz), 2.45 (3H, s ), 2.10-1.99 (1H, m), 1.85-1.69 -206- 200948788 (2H, m), 1.69- 1.45 (6H, m), 1.32 (3H, t, J = 7 Hz). (4) {[(5-(Benzyloxy)-2-{[trans-4-(4-fluorophenoxy)cyclohexyl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amine Ethyl acetate

[({5-(Benzyloxy)-2-[(trans-4-hydroxycyclohexyl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.18 g, 0.40 mmol), 4-fluorophenol (0.089 g, 0.80 mmol), triphenylphosphine (0.21 g, 0.80 mmol) dissolved in tetrahydrofuran (8 mL), and a toluene solution of diethyl azodicarboxylate in Ot. After 40%, 0.35 mL, 0.80 mmol), stirred at room temperature for 15 h. After the reaction mixture was concentrated under reduced pressure, the residue obtained was purified by silica gel chromatography (yield: EtOAc/ethyl acetate), and Rf 値 = 0.30 (hexane/ethyl acetate) The title compound (0.025 g, 0.046 mmol)yield (yield 12%). lH-NMR (500MHz, CDC13) 5 : 8.35 (1H, t, J = 7 Hz), 7.52- 7.45 (2H, m), 7.41-7.32 (3H, m), 6.99-6.91 (2H, m), 6.87 -6.80 (2H, m), 5.12 (2H, s), 4.27 (2H, q, J = 7 Hz), 4.24 (2H, d, J = 7 Hz), 4.12-4.02 (1H, m), 2.83 ( 2H, d, J = 7 Hz), 2.46 (3H, s), 2.18-2.09 (2H, m), 2.03-1.92 (1H, m), 1.85-1.75 (2H, m), 1.51-1.31 (2H, m), 1.32 (3H, t, J = 7 Hz), 1.27-1_13 (2H, m). (5) U(2-{[trans_4_(4-fluorophenoxy)cyclohexyl]methyl}_5_hydroxy-6.methylpyran-4-yl)carbonyl]amino}acetic acid-207- 200948788 Example 1-(3), Example 1-(4), using {[(5-(benzyloxy)-2-{[trans-4-(4-fluorophenoxy)cyclohexyl]) Ethyl acetate (0.025 g, 0.046 mmol MS m/z : 418 (M + H) + ; lH-NMR (500MHz, DMSO-d6) 5 : 11.89 (1H, s), 9.38 (1H, t, J = 6 Hz), 7.11-7.05 (2H, m), 6.95-6.91 (2H, m), 4.25-4.14 (1H, m), 4.00 (2H, d, J = 6 Hz), 2.72 (2H, d, J = 7 Hz), 2.43 (3H, s ), 2.07- 1.98 (2H, m), 1.97- 1.88 (1 H, m), 1.73- 1.65 (2H, m), 1.40- 1.25 (2H, m), 1.24-1·11. (2Η,m) . Example 64 {[(2-{[Reverse-4-(4-chlorophenoxy)cyclohexyl]methyl}-5-hydroxy-6-methylpickyt-4-yl)carbonyl]amino}acetic acid ciOl0〇'^h^〇h imitative Example 63-(4), Example 44-(8), Example 1 (4), 4·Fluorine was replaced by 4-chloropurine (0.13 g, 1.0) The title compound (〇〇31 g, 0.072 mmol MS m/z: 434 (M + H) + ; 1H-NMR (5 00 MHz, DMSO-d6) &lt;5: 11.53 (1H, s), 9.35 (iH, t, J = 6 Hz), 7.28 (2H ,d,J 2 9 Hz), 6.94 (2H,d, J = 9 Hz), 4.25-4.14 (1H, m), 3.94 (2H, d, J = 6 Hz), 2.72 (2H, d, J = 7 Hz), 2.43 (3H, s), 2.08- 1.98 (2H, m), 1.98-1.89 (1H, m), 1.71-1.63 (2H, m), 1.40- 1.25 (2H, m), 1.24-1.13 (2H, m). -208- 200948788 Example 65 {[(2-{[Reverse-4-(4-chloro-2-methylphenoxy)cyclohexyl]methyl) 5-hydroxy-6-methylpyrimidin-4-yl Carbonyl]amino}acetic acid oxime Example 63-(4), Example 44-(8), Example 1-(4), 4-fluorophenol was replaced by 4-chloro-2-methylphenol (0.15 g, 1.0 mmol) 〇MS m/z : 448 (M + H)+ ; lH-NMR (500MHz, DMSO-d6) δ : 9.31 (1H, t, J = 6 Hz), 7.19 (1H, s), 7.14 (1H, d , J = 9 Hz), 6.98 (1H, d, J = 9 Hz), 4.27-4.17 (1H, m), 3.94 (2H, d, J = 6 Hz), 2.72 (2H, d, J = 7 Hz) ), 2.43 (3H, s), 2.10 (3H, s), 2.08- 1.98 (2H, m), 1.98-1.89 (1H, m), 1.71-1.63 (2H, m), 1.40-1.25 (2H, m ), 1.24-1.13 (2H, m).实施 Example 66 ([(2-{[trans-4-(4-t-butylphenoxy)cyclohexyl]methyl) 5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino }acetic acid

Example 63-(4), Example 1-(3), Example 1-(4), 4-fluorophenol was replaced by 4-tert-butylphenol (0.26 g, 1.8 mmol). Compound (0.040 g, 0.088 mmol) mp. MS m/z : 456 (M + H).; -209- 200948788 lH-NMR (500MHz, DMSO-d6) 5 : 11.8 8 (1Η, s), 9 · 3 5 (1Η, t, J = 6 Hz ), 7.25 (2H, d, J = 9 Hz), 6.82 (2H, d, J = 9 Hz), 4.25-4.14 (1H, m), 4.00 (2H, d, J = 6 Hz), 2.72 (2H , d, J = 7 Hz), 2.43 (3H, s), 2.08- 1.98 (2H, m), 1.97- 1.88 ( 1 H, m), 1.71-1.63 (2H, m), 1.40- 1.25 (2H, m), 1.24 (9H, s), 1.24-1.11 (2H, m). Example 67 {[(2-([Reverse-4-(2-tert-butylphenoxy)cyclohexyl]methyl) 5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]aminopurine Acetic acid

Example 63-(4), Example M3), Example 1-(4), 4-fluorophenol was replaced by 2-t-butyl phenol (0.18 g, 1.2 mmol). g, 0.041 mmol) white solid (yield 6.8%). MS m/z : 456 (M + H) + ; lH-NMR (500MHz, DMSO-d6) 5 : 11.91 (1H, s), 9.33 (1H, t, J = 5 Hz), 7.19 (1H, d, J = 8 Hz), 7.12 (1H, t, J = 7 Hz), 6.96 (1H, d, J = 8 Hz), 6.79 (1H, t, J = 7 Hz), 4.44-4.34 (1H, m) , 3.96 (2H, d, J = 5 Hz), 2.74 (2H, d, J = 7 Hz), 2.43 (3H, s), 2.18-2.08 (2H, m), 2.07- 1.98 (1 H, m) , 1.78-1.67 (2H, m), 1.40-1.29 (2H, m), 1.32 (9H, s), 1.24-1.15 (2H, m) o Example 68 -210- 200948788 ([(2-{[反4-(3-tert-butylphenoxy)cyclohexyl]methyl}-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid

Example 63-(4), Example 1-(3), Example 1-(4), 4-fluorophenol was replaced by 3-tert-butylphenol (0.26 g, 1.7 mmol). Compound (0.039 g, 0.086 mmol) mp. MS m/z : 456 (M + H)+ ;

lH-NMR (500MHz, DMSO-d6)5: 11.88 (1H, s), 9.35 (1H, t, J = 7 Hz), 7.17 (1H, d, J = 7 Hz), 6.90 (1H, d, J = 8 Hz), 6.84 (1H, s), 6.74 (1H, dd, J = 8 Hz, 3 Hz), 4.30-4.21 (1H, m), 4.00 (2H, d, J = 7 Hz), 2.72 ( 2H, d, J = 6 Hz), 2.43 (3H, s), 2.08-2.00 (2H, m), 1.99- 1.88 (1 H, m), 1.75-1.66 (2H, m), 1.40- 1.27 (2H , m), 1.24 (9H, s), 1.24-1.11 (2H, m). Example 69 {[(2-{[Reverse-4-(biphenyl-4-yloxy)cyclohexyl]methyl}-5-hydroxy-6-methylpyridin-4-yl)carbonyl]amino group }acetic acid

Example 63-(4), Example 1-(3) 'Example 1-(4), 4-fluorophenol was replaced with biphenyl-4-ol (0.25 g, 1.5 mmol) to give the title compound (0.048 g, 0.10 mmol) white solid (yield 14%). MS m/z: 476 (M + H) + ; 1H-NMR (500MHz, DMSO-d6) 5 : 9.31 (1H, t, J = 4 -211 - 200948788 7.60 (2H, d, J = 8 Hz), 7.56 (2H, d, J = 9 Hz), 7.42 (2H, t, J = 7 Hz), 7.30 (1H, t, J = 7 Hz), 7.00 (2H, d, J = 9 Hz), 4.36- 4.29 (1 H, m), 3.94 (2H, d, J = 4 Hz), 2.74 (2H, d, J = 8 Hz), 2.43 (3H, s), 2.12-2.04 (2H, m), 1.99- 1.90 (1 H, m), 1.75- 1.68 (2H, m), 1.42- 1.30 (2H, m), 1.29-1.14 (2H, m). Example 70 [[(2_{[反-4-(联Benz-3-yloxy)cyclohexyl]methyl}-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid

Example 63-(4), Example 1-(3), Example 1-(4), 4-fluoro-substituted biphenyl-3-ol (0.25 g, 1.5 mmol) (0.047 g, 0.10 mmol) white solid (yield 13%). MS m/z: 476 (M + H) + ; lH-NMR (500 MHz, DMSO-d6) &lt;5: 9.31 (1H, t, J = 4 Hz), 7.64 (2H, d, J = 7 Hz) , 7.45 (2H, t, J = 7 Hz), 7.35 (2H, q, J = 8 Hz), 7.18 (1H, d, J = 8 Hz), 7.15 (1H, s), 6.94 (1H, d, J = 8 Hz), 4.36-4.29 (1H, m), 3.94 (2H, d, J = 4 Hz), 2.74 (2H, d, J 2 Hz), 2.43 (3H, s), 2.12-2.04 ( 2H, m), 1.99-1.90 (1H, m), 1.75- 1.68 (2H, m), 1.42- 1.30 (2H, m), 1.29-1.14 (2H, m). Example 7 1 {[(5-Hydroxy-6-methyl-2-{[trans-4-(4-pyridin-2-ylphenoxy)cyclohexyl]methylpyrimidin-4-yl)carbonyl] Amino}acetic acid-212- 200948788

(1) [({5-(hydroxyl)-6-methyl_2_({cis-4_[(methylsulfonyl)oxy)cyclohexylfluorenylmethyl))) Carbonyl)amino]ethyl acetate

The [({5-(benzyloxy)-2-[(cis-4.hydroxycyclohexyl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino group obtained in Example 63-(3) Ethyl acetate (0.22 g, 0.48 mmol) and triethylamine (O.io mL, 0.71 mmol) dissolved in dichloromethane (10 mL). After that, stir for 30 minutes. After the reaction solution was added with water, it was extracted with dichloromethane. After distilling off the solvent under reduced pressure, the residue obtained was purified by silica gel column chromatography (Sen technology, solvent: hexane/ethyl acetate). Rf 値 = 0.30 (by hexane/ethyl acetate = The title compound (0.24 g, 0.45 mmol)yield (yield: 95%). lH-NMR (500MHz, CDC13) &lt;5: 8.34 (1H, t, J = 7 Hz), 7.52- 7.45 (2H, m), 7.41-7.32 (3H, m), 5.11 (2H, s), 4.24 (2H, q, J =7 Hz), 4.22 (2H, d, J = 7 Hz), 3.03 (3H, s), 2.84 (2H, d, J =7 Hz), 2.45 (3H, s), 2.18 -2.09 (2H, m), 2.03 - 1.92 ( 1 H, m), 1.73- 1.47 (7H, m), 1.32 (3H, t, J = 7 Hz). (2) {[(5-(Hydroxy)-6-methyl-2-{[trans-4-(4-indolyl-2-ylphenoxy)cyclohexyl]methyl}pyrimidine-4 -yl)carbonyl]amino oxime ethyl acetate-213- 200948788

{[(5_(Benzyloxy)-6-methyl-2-({cis-4.[(methyl)alkyl)oxy]cyclohexyl}methyl)acridine-4-ylcarbonyl) Amino]acetic acid ethyl acetate (0·26 g, 0-50 mmol), 4-pyridin-2-yl hydrazine (〇·17 g, 1,0 mmo1) and potassium carbonate (〇.14 g, 1.0 mmol) dissolved in N N-dimethylformamide (10 mL) was stirred at 60 ° C for 15 hours. After the reaction mixture was concentrated under reduced pressure, the residue obtained was purified by silica gel chromatography (yield: sol. The title compound (0.030 g, 0.051 mmol) was obtained as a colorless oil (yield: 1%). 1H-NMR (500MHz, CDC13) &lt;5: 8.67-8.62 (1H, m), 8.36 (1H, t, J = 7 Hz), 7.92 (2H, d, J = 9 Hz), 7.71 (1H, t , J = 6 Hz), 7.67 (1H, d, J = 6 Hz), 7.51-7.44 (2H, m), 7.42-7.32 (3H, m), 7.20-7.15 (1H, m), 6.98 (2H, d, J = 8 Hz), 5.12 (2H, s), 4.28 (2H, q, J = 7 Hz), 4.24 (2H, d, J = 7 Hz), 2.84 (2H, d, J = 7 Hz) , 2.50-2.41 (1H, m), 2.46 (3H, s), 2.28-2.16 (2H, m), 2.03-1.92 (1H, m), 1.87- 1.80 (2H, m), 1.54- 1.44 (2H, m), 1.32 (3H, t, J = 7 Hz), 1.28-1.23 (2H, m). (3) {[(5-Hydroxy-6-methyl-2-{[trans-4-(4-pyridin-2-ylphenoxy)cyclohexyl]methyl}pyrimidin-4-yl)carbonyl]amine Example 1 - (3), Example 1-(4), using {[(5-(benzyloxy)-6.methyl-2-indole [trans-4-(4-pyridine-) Ethyl acetate (0.030 g, 0.051 mmol Solid (yield 83%). MS m/z : 477 (M + H) + ; lH-NMR (500 MHz, DMSO-d6) 5 : 9.38 (1H, t, J = 4 Hz),

8.63-8.59 (1 H, m), 8.00 (2H, d, J = 7 Hz), 7.90-7.82 (1H, m), 7.85-7.79 ( 1 H, m), 7.29-7.24 (1H, m), 7.02 (2H, d, J = 7 Hz), 4.40-4.30 (1H, m), 3.99 (2H, d, J = 4 Hz), 2.74 (2.H, d, J = 8 Hz), 2.44 (3H , s), 2.12-2.04 (2H, m), 1.99- 1.90 (1H, m), 1.75- 1.68 (2H, m), 1.42- 1.30 (2H, m), 1.29-1.14 (2H, m) 72[({5-Hydroxy-6-methyl-2-[(trans-4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)methyl]pyrimidine-4- Carbonyl)amino]acetic acid

Example 71-(2), Example 1-(3), Example M4), 4-(pyridin-2-yl)phenol was replaced by 5-(trifluoromethyl)pyridine-2. The title compound (0.018 g, 0.037 mmol. MS m/z : 469 (M + H) + ; lH-NMR (500MHz, DMSO-d6) 5 : 9.09 (1H, t, J = 4 Hz), 8.57 (1H, s), 8.02 (1H, d, J = 7 Hz), 6.94 (1H, d, J = 7 Hz), 5.10-4.98 (1H, m), 3.67 (2H, m), 2.72 (2H, d, J = 8 Hz), 2.42 (3H, s), 2.12-2.04 (2H, m), 1.99-1.90 (1H, m), 1.75- -215- 200948788 1.68 (2H, m), 1.42- 1.30 (2H, m), 1.29-1.14 (2H, m ° Example 7 3 ({[2-U-trans-4-[(5-chloropyridin-2-yl)oxy]cyclohexyl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl) Carbonyl}amino)acetic acid

Example 71-(2), Example 44-(8), Example 1-(4), 4-pyridine-2-ylphenol was replaced by 5-chloropyridin-2-ol (0.090 g, 0.069) The title compound (0.020 g, 0.046 mmol. MS m/z : 435 (M + H) + ; lH-NMR (500MHz, DMSO-d6) 5 : 9.30 (1H, t, J = 4 Hz), 8.18 (1H, s), 7.76 (1H, d, J = 9 Hz), 6.79 (1H, d, J = 9 Hz), 4.93-4.83 (1H, m), 3.95-3.90 (2H, m), 2.72 (2H, d, J = 8 Hz), 2.43 ( 3H, s), 2.10-2.02 (2H, m), 1.99- 1.90 (1H, m), 1.75- 1.68 (2H, m), 1.42-1.30 (2H, m), 1.29-1.14 (2H, m). Example 74

({[2-({4-[(4-T-butylphenyl)amino]cyclohexyl fluorenylmethyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonylguanidino) Ν Ν ^〇Η Ο (1)({[5-(Benzyloxy)-2-({4-[(4-t-butylphenyl)amino]cyclohexyl}methyl)-6-methylpyrimidine- 4-ethyl]carbonyl}amino)ethyl acetate

200948788

[({5·(Benzyloxy)-6-methyl-2-[(4-oxycyclohexyl)methyl]pyrimidin-4-yl}carbonyl)amino)]] Ethyl acetate (0.13 g, 0.30 mmol), 4-t-butylaniline (0.049 g, 0_037 mmol), sodium tris(ethyloxy)borate (0.089 g, 0.42 mmol), acetic acid (0.017 mL, 0-30) Methyl) was dissolved in 1,2-dichloroethane (2.0 mL) and stirred at room temperature for 1 hour. After the reaction mixture was concentrated under reduced pressure, the obtained residue was purified by silica gel chromatography (yield: EtOAc/EtOAc). The title compound (0.17 g, 0.29 mmol),yield (yield: 97%) of the title compound (yield: 97%) δ: 8.36 (1 Η, t, J = 5 Hz), 7.50- 7.46 (2H, m), 7.40-7.32 (3H, m), 7.19 and 7.18 (for 2H, each d, J = 8 Hz), 6.57 and 6.55 (for 2H, each d, J = 8 Hz), 5.11 (2H, s), 4.27 (2H, q, J = 8 Hz), 4.23 (2H, d, J = 5 Hz), 3.59-3.52 and 3.23-3.14 (count 1H, m), 2.88 and 2.83 (for 2H, each d, J = 7 Hz), 2.45 and 2.44 (for 3H, each 5), 2.15.1.88 (111, 111), 1.85-1.37 (6H, m), 1.32 And 1.31 (count 3H, each t, J = 8 Hz), 1_27 and 1.27 (8H, each s), 1.24-1.10 (2H, m). (2) ({[2-({4-[(4-Tertiphenyl)amino]cyclohexyl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonylguanidinyl) Acetic acid Example 1-(3), Example 1-(4), using (([5-(benzyloxy)_2-({4-[(4-T-butylphenyl))amino]cyclohexyl) Ethyl acetate (0-17 g, 0.29 mmol), m. (yield 57%) MS m/z: 455 (M + H) + ; lH-NMR (500 MHz, DMSO-d6) &lt;5: 9.30 and 9·25 (1H, each t, J = 6 Hz) ), 7.06 and 7.04 (count 2H, each d, J = 6 Hz), 6.53 and 6.47 (count 2H, each d, J = 6 Hz), 3·94 and 3.93 (count 2H, each d, J = 6 Hz) ), 3.45-3.35 and 3.13-3.04 (count 1H, each m), 2.78 and 2.71 (count 2H, each d, J = 7 Hz), 2.43 and 2.42 (count 3H, each s), 2.11-2.02 and 1.92-1.82 (1H, each m), 1.72-1.37 (6H, m), 1.20 and 1.19 (9H, each s), 1.24-1.10 (2H, m). Example 75 ({[2-({ 4-[(4-Tertiphenyl)(methyl)amino]cyclohexyl}methyl)-5-hydroxy-6-methylpyrimidin-4-yl]carbonyl}amino ) Ν-Ν ΟΗ 0 imitative Example 74-(1), Example 1-(3), Example 1-(4) 'The third butyl aniline was replaced by a third butyl-hydrazine-methyl group Aniline (0.090 g, 0.055 mmol) eluted elut elut elut elut elut elut D6)5: 11.89 and 11.88 (count 1H, each s), 9.38 and 9.36 (count 1H, each t, J = 6 Hz), 7.77-7.38 and 7.26- 7.19 (count 2H, each m), 6.80 and 6.58 (for 2H, each m), 4.02 and 4.00 (for 3H, each s), 3.65-3,48 (2H, m), 3.30-3.20 (1H, m), 2.71 and 2.69 (for 2H, each d, J = 7 Hz), 2.43 and 2.43 (count 3H, -218- 200948788 S), 1.94-1.82 and 1.83- 1.72 (count 1H, each m), 1.72- 1.37 (6H, m), 1.23 (9H, s ). Example 7 6 { [(2-{[cis-4-(biphenyl-4-ylamino)cyclohexyl]methyl b 5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino} Acetic acid

(1) {[(2-{[cis-4-(biphenyl-4-ylamino)cyclohexyl]methyl}·5-transyl-6-methylpyrimidin-4-yl)carbonyl]amino group Ethyl acetate and [(2-{[trans-4-(4-biphenyl-4-ylamino)cyclohexyl]methyl}-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino group Ethyl acetate Χχ Ύ Ύ Ύ Ύ 仿 实施 Example 74-(1), Example 1-(3), the third butyl aniline was replaced by biphenyl-4-amine (0.18 g, 1.1 mmol). The title compound (0.38 g, 0.76 mmol) The obtained oily substance was purified by fractional HPLC (YMC-Pack ODS-A; YMC, elution solvent: acetonitrile/buffer (0.05% trifluoroacetic acid, 0.025% triethylamine) = 60/40) to obtain {[(2_) {[ cis-4-(biphenyl-4-ylamino)cyclohexyl]methyl}-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}ethyl acetate (0.24 g, 0.48 M, yield 45%) yellow solid, and {[(2-{[trans-4-(biphenyl-4-ylamino)cyclohexyl]methyl) 5-hydroxy-6-methylpyrimidine-4- Ethyl carbonyl]amino}ethyl acetate (0.13 g, 0.26 mmol, yield 24%) as a white solid. Low polar compound: -219- 200948788 { [(2-{[cis-4-(biphenyl-4-ylamino)cyclohexyl]methyl b 5-hydroxy-6-methylpyrimidin-4-yl)carbonyl Amino acid ethyl acetate

lH-NMR (500MHz, CDC13) 5 : 11.36 (1H, s), 8.57 (1H, t, J

=6 Hz), 7.50 (2H, d, J = 9 Hz), 7.47 (2H, d, J = 9 Hz), 7.39 (2H, d, J = 7 Hz), 7.28 (1H, t, J = 7 Hz), 6.99-6.89 (2H, m), 4.27 (2H, q, J = 6 Hz), 4.22 (2H, d, J = 5 Hz), 3.59-3.49 (1H, m), 2.84 (2H, d , J = 8 Hz), 2.51 (3H, s), 2.20-2.09 (1H, m), 1.90-1.80 (2H, m), 1.78- 1.64 (2H, m), 1.59- 1.49 (2H, m), 1.49- 1.39 (2H, m), 1.32 (3H, t, J = 6 Hz). Highly polar compound: {[(2-{[trans-4-(biphenyl-4-ylamino)cyclohexyl]) Ethyl}-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}ethyl acetate

lH-NMR (500MHz, CDC13)5: 11.35 (1H, s), 8.44 (1H, t, J = 5 Hz), 7.50-7.43 (2H, m), 7.48-7.43 (2H, m), 7.41-7.34 (2H, m), 7.33-7.27 ( 1H, m), 7.09-6.99 (2H, m), 4.29 (2H, q, J = 7 Hz), 4.22 (2H, d, J = 5 Hz), 3.32- 3.19 (1H, m), 2.73 (2H, d, J = 3 Hz), 2.51 (3H, s), 2.11-1.95 (2H, m), 1.98 - 1.8 3 ( 1 H, m), 1.80- 1.72 ( 2H, m), 1.46- 1.30 (2H, m), 1.33 (3H, t, J = 7 Hz), 1.18-1.07 (2H, m). (2) { [(2-([cis-4-(biphenyl-4-ylamino)cyclohexyl]methyl) 5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]aminoindoleacetic acid Example 1-(4), using {[(2-{[cis-4-(biphenyl-4-ylamino)cyclohexyl)methyl) 5-hydroxy-6-methylpyrimidin-4-yl Ethyl acetate ethyl amide (0.24 - 220 - 200948788 g, 0.48 mmol) afforded the title compound (0.23 g, 0.48 mmol) as a yellow solid (yield 9 9 %) MS m/z: 475 (M + H)+ ; lH-NMR (500MHz, DMSO-d6)5 : 12.88 (1H, brs), 11.87

(1H, s), 9.35 (1H, t, J = 7 Hz), 7.53 (2H, d, J = 8 Hz), 7.43-7.33 (4H, m), 7.23-7.16 (1H, m), 6.69 ( 2H, d, J = 8 Hz), 5.70-5.60 ( 1H, m), 4.00 (2H, d, J = 7 Hz), 3.54-3.46 (1H, m), 2.80 (2H, d, J = 8 Hz ), 2.43 (3H, s), 2.15-2.06 (1H, m), 1.74- 1.64 (2H, m), 1.63- 1.58 (2H, m), 1.52-1.42 (4H, m). Example 77 {[(2-{[Reverse-4-(biphenyl-4-ylamino)cyclohexyl]methyl b-5-carbamic-6-methylpyrimidin-4-yl)carbonyl]amino} Acetic acid

Example 1-(4), using [trans-4-(biphenyl-4-ylamino)cyclohexyl]methyl}-5-hydroxy-6-methylpyrimidine as obtained in Example 76-(1) Ethyl acetate (0.13 g, 0.26 mmol). MS m/z: 475 (M + H) + ; lH-NMR (500 MHz, DMSO-d6) &lt;5: 11.92 (1H, s), 9.35 (1H, t, J = 4 Hz), 7.52 (2H, d, J = 8 Hz), 7.40-7.3 3 (4H, m), 7.23-7.16 (1H, m), 6.62 (2H, d, J = 8 Hz), 5.61-5.54 (1H, m), 3.97 ( 2H, d, J = 4 Hz), 3.26-3.13 (1H, m). 2.73 (2H, d, J =7 Hz), 2.44 (3H, s), 2.04-1.95 (1H, m), 1-95 -1.85 (2H, m), -221 - 200948788 1.72- 1.62 (2H, m), 1.25-1.10 (4H, m). Example 7 8 ({[2·{[trans-4-(4-fluorophenyl)cyclohexyl]methyl}-5-hydroxy-6 (methylthiol)pyrimidin-4-yl]carbonyl}amino group Acetic acid

(1) 5-(decyloxy)-2-{[4-(4-fluorobenzyl)cyclohexyl]methyl}_6_pyridylpyrimidine 4-carboxylic acid tert-butyl ester

Example 51-(1), Reference Example 4-(4), Reference Example 1 (3), EtOAc (m. 6.7 mmol) white solid (yield 54%).

lH-NMR (500MHz, CDC13) (5: 12.1 (1H, s), 7.48 (2H, d, J = 7 Hz), 7.3 8-7.33 (3H, m), 7.11-7.08 (2H, m), 6.97 -6.93 (2H, m), 5.26 (2H, s), 2.63 (2H, d, J= 7 Hz), 2.42 (1H, t, J =12 Hz), 1.95 (1H, m), 1.86 (2H, d, J = 12 Hz), 1.72-1.59 (2H, m), 1.53 (9H, s), 1.46- 1.39 (2H, m), 1.27-1.19 (2H, m) o (2)({ [5- (Benzyloxy)-2-([trans-4-(4-fluorophenyl)cyclohexyl]methyl}-6-hydroxypyrimidin-4-yl]carbonyl}amino)ethyl acetate

-222- 200948788 Reference Example 1-(4), 5-(Benzyloxy)-2-{[4-(4-fluorophenyl)cyclohexyl]methyl}-6-hydroxypyrimidine-4-carboxylate The title compound (1.6 g, 3.0 mmol) was obtained as white crystals (yield: 44%). MS m/z : 522 (M + + H):

lH-NMR (500MHz, CDC13) 5 : 11.7 (1H, s), 8.04 (1H, t, J

=5 Hz), 7.57 (2H, d, J = 7 Hz), 7.37-7.30 (3H, m), 7.11-7.09 (2H, m), 6.95 (2H, t, J = 9 Hz), 5.36 (2H , s), 4.26 (2H, q, J = 7 Hz), 4.18 (2H, d, J = 5 Hz), 2.62 (2H, d, J = 7 Hz), 2.46-2.41 (1H, m), 1.96 (1H, m), 1.89- 1.83 (4H, m), 1.48-1.40 (2H, m), 1·31 (3H, d, J = 7 Hz), 1.22- 1.20 (2H, m). (3) ({[5-(Benzyloxy)-2-{[trans-4-(4-fluorophenyl)cyclohexyl]methyl}-6-{[(trifluoromethyl)sulfonyl] Ethyl}pyrimidin-4-yl]carbonyl oxime) ethyl acetate

Referring to Example 2-(3), ({[5-(benzyloxy)-2-{[trans-4-(4-fluorophenyl)cyclohexyl]methyl}-6-hydroxypyrimidine-4) Ethyl-carbonyl]amino)acetate (0.89 g, 1.7 mmol) 1H-NMR (500MHz, CDC13) &lt;5: 8.16 (1H, t, J = 4 Hz), 7.49 (2H, d, J = 4 Hz), 7.39-7.34 (3H, m), 7.17-7.14 (2H , m), 6.98-6.95 (m, 2H), 5.25 (2H, s), 4.28 (2H, q, J = 8 Hz), 4.24 (2H, d, J = 4 Hz), 2.87 (2H, d, J = 4 Hz), 2.50-2.45 (1H, m), 2.02-1.96 (1H, m), 1.89 (2H, d, J = 8 Hz), 1.81 (2H, d, J = 12 Hz), 1.48- 1.41 (2H, m), 1.33 (3H, t, J = 7 Hz), 1.39-1.19 -223- 200948788 (2H,m). (4) ({[5-(Benzyloxy)-2-{[trans-4-(4-fluorophenyl)cyclohexyl]methyl}-6-(methylsulfanyl)pyrimidin-4-yl] Carbonyl}amino)ethyl acetate

({[5-(Benzyloxy)-2-{[trans-4-(4-fluorophenyl)cyclohexyl]methyl}-6-{[(trifluoromethyl)sulfonyl]oxy) Ethyl pyrimidine-4-yl]carbonyl}amino)acetate (0.90 g, 1.4 mmol) and sodium methanethiolate (0.14 g, 2.1 mmol) dissolved in N,N-dimethylformamide (15 mL) Stir at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (Biotage, elution solvent: hexane/ethyl acetate), and Rf 値 = 0.45 (hexane/ethyl acetate = 4 / The title compound (0.34 g, 〇· 61 mmol) (yield: 44%) was obtained. 1H-NMR (400MHz, CDC13) δ : 8.39 (1H, t, J = 4 Hz), 7.60 (2H, d, J = 4 Hz), 7.40-7.32 (3H, m), 7.17-7.15 (2H, m ), 6.96 (2H, d, J = 8 Hz), 5.17 (2H, s), 4.27 (2H, q, J = 8 Hz), 4.23 (2H, d, J = 4 Hz), 2.83 (2H, d , J = 4 Hz), 2.54 (3H, s), 2.54-2.39 (1H, m), 2.10-2.01 (1H, m), 1.88 (4H, d, J =12 Hz), 1.50-1.42 (2H, m), 1.32 (3H, t, J = 8 Hz), 1.39-1.19 (2H, m). (5) ({U-{[trans-4-(4-fluorophenyl)cyclohexyl]methyl}-5-hydroxy-6-(methylsulfanyl)pyrimidin-4-yl]carbonyl}amino) Ethyl acetate-224- 200948788 F Example 26-(1) 'Used ({[5-(benzyloxy)-2-{[trans-4-(4-fluorophenyl)cyclohexyl)methyl 6 Ethyl acetate (0.34 g, 0.61 mmol), m. 1H-NMR (500MHz, CDC13) &lt;5 : 11.63 (1 Η, s), 8 · 45 (1Η, t,

J = 4 Hz), 7.17-7.14 (2H, m), 6.98-6.94 (2H, m), 4.28 (2H, q, J = 7 Hz), 4.21 (2H, d, J = 4 Hz), 2.77 ( 2H, d, J = 8 Hz), 2.58 (3H, s), 2.50-2.45 (1H, m), 2.00-1.93 (1H, m), 1.86 (4H, d, J = 12 Hz), 1.48-1.40 (2H, m), 1.33 (3H, t, J = B Hz), 1.28-1.18 (2H, m). (6)({[2-{[trans-4-(4-fluorophenyl)cyclohexyl]methyl}-5-hydroxy-6-(methylsulfanyl)pyrimidin-4-yl]carbonyl}amino group Acetic acid

Example 1-(4), using ({[2-{[trans-4-(4-fluorophenyl)cyclohexyl]methyl}-5-hydroxy-6-(methylsulfanyl)pyrimidine-4 Ethyl-carbonyl)amino)acetate (0-25 g, 0.54 mmol) Mp 1 86- 1 88 °C; 1H-NMR (400MHz, DMSO-d6) &lt;5: 9.53 (1H, s), 7.26-7.23 (2H, m), 7.09-7.05 (2H, m), 3.88 ( 2H, s), 2.70 (2H, d, J = 4 Hz), 2.50 (3H, s), 2.50-2.7 (1H, m), 1.98-1.91 (1H, m), 1.77 (4H, d, J = 12 Hz), 1.46- 1.35 (2H, m), 1.21-1.14 (2H, m) ° (Test Example) -225- 200948788 The usefulness (pharmacological activity) of the compound of the present invention was confirmed by the following test. The in vitro erythropoietin (EPO)-inducing activity of the test compound was evaluated using Hep3B cell line (ATCC, Manassas, VA) derived from human liver cancer. Hep3B cells were cultured in DMEM (Dulbecco, Modified Eagle, medium) in the presence of 10% FBS (bovine fetal serum) at 37 ° C for one night (24-well plates, 1.0 X 105 cells/well). Exchanged with fresh DMEM (+10% FBS) containing test compounds dissolved in 〇.5% DMSO (dimethyl hydrazine) (modulated to a concentration of 12.5 // M) or solvent control (control: 0.5% DMSO) , cultured at 37 ° C for 24 hours. After recovering the culture supernatant, the EPO concentration in the culture supernatant was quantified using a human EPO ELISA kit (StemCell Technologies). The compounds of Examples 4, 9, 26, 31, 35, 37, 39, 44, 53, 57 '59 were used for the test compounds. The EP0 concentration of each example is expressed as a multiple of the EP0 concentration in the control group. The results are shown in Table 1. The compounds of the present invention exhibit excellent EP0 capacity. -226- 200948788 (Table 1) Test compound ΕΡΟ concentration (times) Control group (0.5% DMSO) 1 Example 4 42 Example 9 36 Example 26 30 Example 31 97 Example 35 160 Example 37 64 Implementation Example 39 86 Example 44 192 Example 53 75 Example 56 189 Example 57 303 Example 69 50 Ο

[Industrial Applicability] The novel compound having a 5-hydroxypyrimidine-4-carboxamide structure of the present invention has excellent cockroach productivity and is useful for diseases caused by the low erythropoietin. Specifically, the compound of the present invention or a pharmacologically acceptable salt thereof is used as anemia, especially renal anemia (dialysis period, preservation period), anemia of immature children, anemia accompanied by chronic diseases, anemia associated with cancer chemotherapy, and cancer anemia. -227- 200948788 Anti-and/or therapeutic agents are useful. It can also be used as a prophylactic and/or therapeutic agent for debilitating brain diseases. [Simple diagram description] te 〇

JWS [Main component symbol description] 4rr- 〇 〇

-228-

Claims (1)

200948788 VII. Patent application scope: 1. A compound of the following formula (1) or a pharmacologically acceptable salt thereof, (1) [In the formula (1), R1 is -X-Q1'-X-Q'-Y-Q2, or -X-Q'-YQ^Z-Q3 is based on -OCH2-X is a single bond, -CH2-, -(CH2)2 -, -(CH2)3-, -CH2C),,, -Ο-, -S-, or -CO- Q1 are one or two of which may be selected from the substituent group α to take π stomach ring or two ring a hydrocarbon ring group (the hydrocarbon ring group includes a 3 to 10 &amp; θ square aromatic hydrocarbon ring and a non-aromatic hydrocarbon ring), and the substituent group α is a halogen atom, a pendant oxy group, a hydroxyl group, 卤 卤 & & & & & & & & & & & : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : -(CH2)2-, -(ch2)3-, -ctho., _〇CH2_, -0(CH2)2-, -Ο-, -S-, -NH-, -NCH3-, or -c〇 _ , Q2 is a monocyclic or bicyclic hydrocarbon ring group which may have one or two substituents selected from the substituent group (the hydrocarbon ring group includes an aromatic hydrocarbon ring of 3 to 10 members and a non-aromatic group) a hydrocarbon ring), or a monocyclic or bicyclic heterocyclic group which may have one or two substituents selected from the substituent group /3 (the heterocyclic group includes 4 to 10 membered aromatic heterocyclic rings and non-aromatic groups) a heterocyclic ring containing one or two atoms selected from the group consisting of a nitrogen atom, a -229-200948788 sulfur atom and an oxygen atom, and the substituent group is a halogen atom, a pendant oxy group, a hydroxyl group, an amine group, a cyano group, Cl~C6 yard base, halogenated Cl~C6 yard base, Cl~Ce institute oxy group, halogenated alkoxy group, 〇~(:6 alkylamino group, (匕~(:6 alkyl)((:!~C6) a group of an alkyl group, an amine group, and a C2~C? alkano group, Z is a single bond, -CH2-, -(CH2)2-, -OCH2-, -〇-, -S-, -NH- - n(ch3)-, or -CO-, Q3 is a phenyl group which may have one or two substituents selected from the substituent group T, and may have one or two selected from the substituent group 7* a C3 to C7 cycloalkyl group of the substituent, a c3 to c7 cycloalkenyl group which may have one or two substituents selected from the substituent group r, or one or two substituents which may be selected by the substituent group r a monocyclic or bicyclic heterocyclic group (the heterocyclic group includes 4 to 10 membered aromatic heterocyclic rings and non-aromatic heterocyclic rings, and a group selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom) 1 or 2), the substituent group r is a halogen atom, a pendant oxy group, a hydroxyl group, an amine group, a cyano group, a Ci~c6 alkyl group, a halogenated alkyl group, a hydrazine~(:6 alkoxy group, a halogenated alkoxy group, ο~(:6 alkylamino group, alkyl)(0~0 alkyl)amine group, and C2~C7 alkyl fluorenyl group, R2 is (^~(^alkyl, cyclopropyl, methylthioalkyl, A fluoromethyl group or a difluoromethyl group, and R3 is a hydrogen atom or a methyl group. 2. A compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein X is a single bond, -CH2-, or -( CH2)2-. 3. If the compound of claim 1 or The pharmacologically acceptable salt, wherein -230-200948788 is a single bond. 4. The compound of any one of claims 1 to 3, or a pharmacologically acceptable salt thereof, wherein Q1 is selected from the group of substituents One or two substituents of cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, naphthyl, tetrahydronaphthyl, decahydronaphthyl, Hydroquinone, decenyl, or norbornyl. 5. A compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein Q1 is a cyclohexyl or cyclohexene which may have one or two anthracene substituent selected from the substituent group α. Base, phenyl, or naphthyl. 6. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein Q1 is a cyclohexyl or cyclohexenyl group which may have one or two substituents selected from the substituent group α Or phenyl. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 6, wherein the substituent group α is a halogen atom, a hydroxyl group, a hydrazine (?6 alkyl group, a halogenated (^~ decyl group, A compound of the above formula (1), or a pharmacologically acceptable salt thereof, wherein the substituent group α is a fluorine atom or a chlorine atom, A compound of the hydroxy group, the second butyl group, the difluoromethyl group, and the hexyloxy group. The compound of any one of claims 1 to 8 or a pharmacologically acceptable salt thereof, wherein R1 is -XQ^ YQ:, or _x_q1_y_q2_Zq3, the base 'Y is a single bond, -CH2-, -(CH2)2-, -〇(ch2)2-, -〇_, -NH_, or -NCH3-. A compound of claim 9 or a pharmacologically acceptable salt thereof, wherein Y is a single bond, -〇-, -CH2-, or -NH-. -231- 200948788 11. As claimed in claims 1 to 10 A compound or a pharmacologically acceptable salt thereof, wherein R1 is a group represented by -X-Q'Y-Q2 or -XC^-YQ^z-Q3, and Q2 is one which may be selected from the group of substituents or 2 substituents of cyclopentyl, ring , cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, naphthyl, tetrahydronaphthyl, decahydronaphthyl, hydroquinone, nonenyl, norbornyl, tetrahydrofuran , tetrahydropyranyl, didecylalkyl, dioxanyl, dioxaheptyl, aziridinyl, zzaridyl, piperidinyl, anthracene, piperylene, dihydrogen Carbazolyl, dihydrothiazolyl, morpholinyl, pyrrolyl, dihydropyrrolyl, pyridyl, dihydropyridyl, tetrahydropyridyl, thienyl, furyl, pyrimidinyl, hydrazine, pyridyl , pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, chromoalkyl, isochroman, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzo Thienyl, fluorenyl, isodecyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolinyl, benzoxazolyl, quinoxalinyl, benzothiazolyl, a benzodioxanyl group, a hydrazine-trap group, a thienopyridyl group, a dihydrothienopyridinyl group, a furopyridinyl group, or a dihydrofuropyridinyl group. 12. The scope of claim 11 Or a pharmacologically acceptable salt thereof, wherein Q2 is a cyclohexyl group, a cyclohexenyl group, a phenyl group, an acridinyl group, a pyridyl group or a pyrimidinyl group which may have one or two substituents selected from the substituent group /3 13. A compound according to claim 11 or a pharmacologically acceptable salt thereof, wherein Q2 is a phenyl, piperidinyl, pyridyl or pyrimidinyl group which may have one or two substituents selected from the group of the group of stones. -232- 200948788 A compound or a drug thereof or -X-Q'-Y-Q'Z-Q3 1 4 · As permitted in the scope of claims 1 to 13 of the patent, wherein R1 is - XQ^Y-Q2, the substituent group β is a halogen atom, a hydroxyl group, a cyano group, a fluorene-c6 alkyl group, a halogenated Cl~C6 alkyl group, or a halogenated group. a group of ~ decyl, Ci~C6 alkoxy, halogenated (^~(:6 alkoxy, Cz~C7 alkyl fluorenyl) 15. The compound of claim 14 or a pharmacologically acceptable salt thereof, wherein the substituent group /3 is a fluorine atom, a chlorine atom, a hydroxyl group, a cyano group, a methyl group, a second butyl group, a methoxy group, a trifluoro group. A group of methyl, trifluoromethoxy and ethyl hydrazino groups. The compound or the pharmacologically acceptable salt thereof, wherein R1 is a group represented by -X-QLY-Q, Z_q3, and z is a single bond, -CH2-, -OCH2-, -〇·, -NH-, or - CO-. 17. A compound according to claim 16 or a pharmacologically acceptable salt thereof, wherein z is a single bond, -CH2-, -0, or -CO-. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 17, wherein R1 is a group represented by -XQ^YQ^Z-Q3, and Q3 is selected from the group of substituents r. One or two substituents of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, phenyl, tetrahydrofuranyl, tetrahydrogen Pyranyl, dinonylalkyl, dioxanyl, dioxaheptyl, aziridinyl, pyrrolidinyl, piperidinyl, anthracenyl, dihydrocarbazolyl, dihydrothiazolyl, Morpholinyl, pyrrolyl, dihydropyrrolyl, pyridyl, dihydropyridyl, tetrahydropyridyl, thienyl, furyl, pyrimidinyl, hydrazine, pyridinyl-233-200948788, pyrazolyl, Thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, chromoalkyl, isochroman, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, anthracene , isodecyl, quinolyl, tetrahydroquinolyl, iso- sialino, tetrahydroisoquinolinyl, imidazopyridyl, benzoxazolinyl, quinoxalinyl, benzothiazole , Benzodioxan Shu group, indole group farming, saliva thieno pyridyl, dihydro-thieno pyridyl, furyl and pyridyl, dihydro or furopyridinyl. 19. The compound of claim 18 or a pharmacologically acceptable salt thereof, wherein Q3 is a phenyl or pyridyl group which may have one or two substituents selected from the substituent group r. 20. The compound of claim 18 or a pharmacologically acceptable salt thereof, wherein Q3 is a pyridyl group which may have one or two substituents selected from the substituent group r. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 20, wherein R1 is a group represented by -X-Q'YQ^Z-Q3, and the substituent group 7 is a fluorine atom, And a group of hydroxyl groups. The compound of any one of claims 1 to 21, wherein R2 is methyl, ethyl, methylthioalkyl, fluoromethyl or difluoromethyl, or a pharmacologically acceptable salt thereof. The compound of any one of claims 1 to 21, wherein R2 is a methyl group or a methylthioalkyl group, or a pharmacologically acceptable salt thereof. The compound of any one of claims 1 to 21, wherein R3 is a hydrogen atom, or a pharmacologically acceptable salt thereof. 25. The compound of claim 1 or a pharmacologically acceptable salt thereof, wherein -234-200948788 R1 is a group represented by -X-Ql-Y-Q2, and X is a single bond, -CH2-, or -(CH2) 2-, Q is a phenyl group, a cyclohexenyl group or a cyclohexyl group which may have one or two substituents selected from the substituent group α, and the substituent group α is a group of a fluorine atom and a chlorine atom. Υ is a single key, -CH2-, -0-, or -ΝΗ-, Q2 is a cyclohexyl group, a cyclohexyl group, a phenyl group, a decyl group, a pyrimidine group or a pyrimidyl group which may have one or two substituents selected from the substituent group, and the substituent group β is a gas. A group of atoms, atmosphere atoms, methyl groups, rr butyl groups, and trifluoromethyl groups. 26. The compound of claim 25 or a pharmacologically acceptable salt thereof, wherein 'Q2 is a phenyl, piperidinyl, pyridyl, or pyrimidine which may have one or two substituents not selected by the substituent group base. 27. The compound of claim i or a pharmacologically acceptable salt thereof, wherein R1 is a group represented by -XC^-YQ^Z-Q3, X is a single bond, and Q1 is selected from the group α of substituents One or two substituents of a phenyl group, a cyclohexenyl group or a cyclohexyl group, and the substituent group α is a group consisting of a hydroxyl group, Υ is a single bond, -〇-, or -ΝΗ-, Q2 is a phenyl group, Piperidinyl or pyridyl, Ζ is a single bond, -CH2-, -0-, -ΝΗ-, or -CO-, Q3 is a benzene which may have one or two substituents selected by the substituent group r Or a pyridyl group, -235 - 200948788 The substituent group r is a group of a fluorine atom and a hydroxyl group. 28. The compound of claim 27 or a pharmacologically acceptable salt thereof, wherein Q2 is a phenyl group or a decyl group which may have one or two substituents selected from the group of substituent groups, and Q3 may be The phenyl or pyridyl group of one or two substituents selected by the substituent group r. 29. The compound of claim 1 or a pharmacologically acceptable salt thereof, which is selected from the group consisting of the following compounds or pharmacologically acceptable salts thereof: ({[2-(biphenyl-4-ylmethyl)-5-hydroxyl) -6-methylpyrimidin-4-yl]carbonyl}amino)acetic acid, [(•{2-[(4'·fluorobiphenyl-4-yl)methyl]-5-hydroxy-6.methylpyrimidine 4-yl}carbonyl)amino]acetic acid, ({[2-(4-cyclohex-1-iso-1-yl))-5-ylamino-6-methylpyran-4-yl] Carbonyl}amino)acetic acid, {[(5-hydroxy-6-methyl-2-{[4'-(trifluoromethyl)biphenyl-4-yl]methyl}pyrimidin-4-yl)carbonyl] Amino}acetic acid, ({[5-hydroxy-6-methyl-2-(1,1':4',1"-bitriphenyl-4-ylmethyl)pyrimidin-4-yl]carbonyl} Amino)acetic acid, [({5-hydroxy-6-methyl-2-(2-phenylcyclohex-1-en-1-yl)methyl]pyrimidin-4-yl}carbonyl)amino] Acetic acid, [({2-[(4'-t-butylbiphenyl-4-yl)methyl]-5-hydroxy-6-methylpyrimidin-4-yl}carbonyl)amino]acetic acid, [( {2-[4-(5-Benzylpyridin-2-yl)benzyl]-5-hydroxy-6-methylpyrimidine_4_-236- 200948788 yl)carbonyl)amino]acetic acid, {[(5- Hydroxy-6-methyl-2-{ [4'-(pyridine-3 -ylmethyl)biphenyl-4-yl]methyl}pyrimidin-4-yl)carbonyl]aminopurine acetic acid, {[(5-hydroxy-6-methyl-2-{[4'-(pyridine- 4-ylmethyl)biphenyl-4-yl]methyl}pyrimidin-4-yl)carbonyl]aminopurine acetic acid, {[(5-hydroxy-6-methyl-2-{[4'-(pyridine) -2-ylmethyl)biphenyl-4-yl]methyl}pyrimidin-4-yl)carbonyl]amino}acetic acid, Ο [({5-Hydroxy-6-methyl-2-[4-(4-phenylpiperidin-1-yl)benzyl]pyrimidin-4-yl}carbonyl)amino]acetic acid, {[(2 -{[trans-4-(4'-fluorobiphenyl-4-yl)cyclohexyl]methyl b 5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid, {[(2) -{[trans-4-(4-benzylphenyl)cyclohexyl]methyl}-5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid, {[(5-hydroxy-) 6-Methyl-2-{[trans-4-(4-pyridin-2-ylphenyl)cyclohexyl]methylpyrimidin-4-yl)carbonyl]amino}acetic acid, {[(5-hydroxy-) 6-Methyl-2-{[trans-4-(4-pyridin-3-ylphenyl)cyclohexyl]methylpyrimidin-4-yl)carbonyl]amino}acetic acid, {[(5-hydroxy-) 6-Methyl-2-{[4-(4-phenoxyphenyl)cyclohex-3-en-1-yl]methyl}pyrimidin-4-yl)carbonyl]amino}acetic acid, {[(5 -hydroxy-6-methyl-2-{[4-(4-phenoxyphenyl)cyclohexyl]methyl}pyrimidin-4-yl)carbonyl]amino}acetic acid, {[(2-{[反- 4-(biphenyl-4-yloxy)cyclohexyl]methyl b 5-hydroxy-6-methylpyrimidin-4-yl)carbonyl]amino}acetic acid, and {[(2-{[re-4) -(biphenyl-4-ylamino)cyclohexyl]methyl}-5-hydroxy-6-methyl-237- 200948788 pyrimidin-4-yl)carbonyl]amino group Acetic acid. A pharmaceutical composition comprising a compound according to any one of claims 1 to 29, or a pharmacologically acceptable salt thereof, as an active ingredient. 31. The medicine of claim 30, which is used for the prevention and/or treatment of anemia. 32. The medicine of claim 31, wherein the anemia is renal anemia, anemia of immature children, anemia associated with chronic diseases, anemia associated with cancer chemotherapy, or cancer anemia. 33. The pharmaceutical of claim 30, which is for use in the production of a erythropoietin erythropoietin. The compound of any one of claims 1 to 29, or a pharmacologically acceptable salt thereof. Used, it is used in the manufacture of medicines. 35. If the compound of claim 34 or its pharmacologically acceptable salt is applied, the Chinese medicine is a medicine for preventing and/or treating anemia. 36. For use in Article 34 of the patent application, anemia is renal anemia, anemia in unripe children, anemia associated with chronic diseases, anemia associated with cancer chemotherapy, or cancer anemia. 〇 37. A method for producing erythropoietin which is administered to a mammal or a bird by an effective amount of a compound selected according to any one of claims 1 to 29, or a pharmacologically acceptable salt thereof. 38. The method of claim 37, for the prevention and/or treatment of anemia. 39. The method of claim 37, wherein the anemia is renal anemia, anemia of immature children, anemia associated with chronic diseases, anemia associated with cancer chemotherapy, 238-200948788, or cancerous anemia. 40. The method of claim 37, wherein the mammal is a human, a horse, a cow or a pig, and the bird is a chicken. ❹ -239- 200948788 IV. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the symbol of the symbol of the representative figure Μ 〇 j\\\ Ο 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: